Emerging Modalities in the Treatment of Pain Janice Huntingford, DVM, DACVSMR, CVA, CCRT, CVPP, CAVCA Essex Animal Hospital Essex, Ontario

What exists for painful veterinary patients beyond rest and NSAIDs? What can I do for those really painful patients? Where can I find help and answers for my pain questions? What are the standards of care for pain? Are there any non pharmalogical modalities that really work for pain? These are all very common questions for veterinary practitioners to ask in this changing world. We will deal with what’s new and what is on the horizon for pain in veterinary practice. Standards of care for pain in dogs and cats is now outlined in the new AAHA/AAFP pain guidelines. Here is an excerpt summarizing the guidelines: The 2015 guidelines summarize and offer a discriminating review of much of this new knowledge. Pain management is central to veterinary practice, alleviating pain, improving patient outcomes, and enhancing both quality of life and the veterinarian-client-patient relationship. The management of pain requires a continuum of care that includes anticipation, early intervention, and evaluation of response on an individual-patient basis. The guidelines include both pharmacologic and nonpharmacologic modalities to manage pain; they are evidence-based insofar as possible and otherwise represent a consensus of expert opinion. Behavioral changes are currently the principal indicator of pain and its course of improvement or progression, and the basis for recently validated pain scores. A team- oriented approach, including the owner, is essential for maximizing the recognition, prevention, and treatment of pain in animals. Postsurgical pain is eminently predictable but a strong body of evidence exists supporting strategies to mitigate adaptive as well as maladaptive forms. Degenerative joint disease is one of the most significant and under-diagnosed diseases of cats and dogs. Degenerative joint disease is ubiquitous, found in pets of all ages, and inevitably progresses over time; evidence based strategies for management are established in dogs, and emerging in cats. These guidelines support veterinarians in incorporating pain management into practice, improving patient care.

Pain scoring is important and veterinarians need to use pain scales Although the Glasgow Composite Pain Scale is the only validated Acute pain scale, the Colorado State Acute Pain scales for post surgical pain are easier to use. They rely on pictures and should be scored by the same person as the inter rater scores could vary. Chronic pain scales include the Helsinki Chronic Pain Scale, the Canine Brief Pain Inventory, the Cincinatti Orthopaedic Disability Index and others. The important thing is to familiarize yourself with one of these scales and use it consistently.

New or new to you techniques to consider Local anesthetics with every surgery—Line blocks, Ring blocks, testicular and ovarian blocks. For chronic orthopedic disability regional anesthesia with bupivicaine can be used to relieve pain so muscles can be strengthened—consider blocking femoral or sciatic nerves—may need to use a nerve finder to do this. Epidurals—not really new for orthopaedic surgery but consider these for blocked cats ( sacral epidural). For dogs with painful lumbosacral disease consider epidurals with methyprednisilone—it will not improve neurological function but will relieve pain.  Ketamine—Subanesthetic doses as CRIs for painful surgeries—things that are likely to trigger maladaptive pain syndrome.  Use of Amitriptyline for Chronic pain—much lower doses than needed for anxiety.  Joint injections with HA and corticosteroids

New information  Pruritis receptors are a subset of nociceptors that also respond to pain.  Substance P and Glutamate can cause pain and itch.  Itch can be inhibited by pain--mild scratching inhibits itch. In order to inhibit the itch signalling pathway you need to have both itch and pain as these overlap, so consider this when dealing with chronically itchy animals—this may be why amitriptyline works for pain. Glial cell dysregulation Originally thought that non neuronal cells (glia) had no input into the nervous system. However research has shown that microglia and astrocytes have an effect on the nervous system and how it handles opiates. Glial cells are key in the development of pathologic pain. In every clinically relevant model of enhanced pain, the glial cells are activated, so if you block the glia cells you block pain. Glial cells monitor the CNS--they are very active cells--when they find danger they actively attack it--they release all kinds of substances. The important thing to know is they amplify the pain transmission to brain, they up regulate the NMDA receptor numbers and down regulate GABA and glia glutamate transporters.

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Glial cells enhance pain and PREVENT opiates from working. What activates glia cells?—lots of stuff--Opioids, endogenous danger signals ( leakage of blood—anything that should not be in the nervous system that causes cell stress and damage). Most common endogenous danger signals are peripheral nerve injury , overuse of medication, s diabetic neuropathy, spinal cord injury, bone cancer, arthritis, and pancreatitis. These conditions cause pro inflammatory cytokines to be released. Opioids activate the glial cells so this can actually block the pain control from the glial cells--if you block the spinal IL-1 the analgesia comes back. Opioid effects are different on neurons vs glial cells. The glial cell receptor is TLR4 ( not me not right no ok receptor) --it is a major player in identifying endogenous danger signal and recognizes all lipids.Glial TLR4 is a driver of neuropathic pain. If the glial cells are blocked by + naloxone then it might be a stand alone treatment for neuropathic pain.Other cells involved are in blood vessels and these produce IL-1 ( pro inflammatory cytokines) and these can be blocked by naloxone. When glial cells are active and you give opioid for pain it makes pain worse because the glial cells are induced to produce more IL 1 and block the opioid receptors. Primed state can occur for a period of time after prior activation--the glial cells are not activated they are waiting and the reaction comes back with a vengeance. Primed glial cells can be activated by aging, opioids , stress, trauma and inflammation Clinical relevance--prior surgery changes pain to chronic pain --this can be prevented by glial activation inhibitor.. Another interesting point--morphine can worsen post surgical pain. This is mediated by TLR4--so to control this you need to give a TLR4 blocker when you give morphine. IL-10—anti inflammatory interleukin—this is being developed for inter thecal injection. Grapiprant—EP4 blocker that works in inflammatory cascade with no NSAID side effects Theracurmin—biologically active curcumin—water soluble

Non pharmacological  Acupuncture—more common and more accepted.  PT modalities easily added to general practice—Laser, exercise therapy, hot and cold therapy, TENS  Myofascial pain—this is something new to veterinary medicine. It is a myalgic condition in which muscle and tendon are the primary cause of pain. The syndrome is centered around the myofascial trigger point ( MTrP). A myofascial trigger point is an extended contraction of a few muscle fibers that results in a painful knot. Dry needling is what is done to eliminate them. If you are interested there is an entire lecture on this topic.  Regenerative Medicine—PRP and Stem cell

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Pain in Cats: An Integrative Approach Janice Huntingford, DVM, DACVSMR, CVA, CCRT, CVPP, CAVCA Essex Animal Hospital Essex, Ontario

Pain is a multidimensional sensory experience that is intrinsically unpleasant and associated with hurting and soreness. It may vary in intensity (mild, moderate, or severe), quality (sharp, burning, or dull), duration (transient, intermittent, or persistent), and referral (superficial or deep, localized or diffuse). Pain is divided into 2 categories: Adaptive and Maladaptive Pain. Adaptive pain is that which serves a purpose—to protect the body from harmful substances or protect the body while healing occurs. Adaptive pain can be either nociceptive or inflammatory. Nociceptive pain is pain that is transient from noxious stimuli. Inflammatory pain is spontaneous in response to tissue inflammation or injury. Both of these could be considered acute pain and will occur naturally post injury or inflammation and are limited in their scope and time frame. These types of pain are pain with a purpose—to protect and allow rest for healing. Maladaptive pain is pain as a disease and it serves no useful purpose.Such pain may occur in response to damage to the nervous system (neuropathic pain) or result from abnormal operation of the nervous system (functional pain). Maladaptive pain is the expression of abnormal sensory processing and usually is persistent or recurrent. Maladaptive pain can result from peripheral or central sensitization. In peripheral sensitization inflammation and tissue damage produce a variety of nociceptor-sensitizing substances, including prostaglandins, histamine, serotonin, bradykinin, proteases, cytokines (tumor necrosis factor α), and nerve growth factor. This “sensitizing soup” lowers the nociceptor threshold to painful stimuli and activates “silent” or “sleeping” nociceptors, resulting in hyperalgesia( exaggerated response to noxious stimuli) and allodynia ( painful response to normal stimuli). Central sensitization occurs when severe (high-intensity) or chronic painful stimuli activate C fibers, causing the release of glutamate, substance P (Sub P), and brain-derived neurotrophic factor (BDNF) at central nerve terminals; this results in the activation of number of receptors producing acute and long-lasting dull, aching, burning pain sensations. Collectively, the activation of these receptors increases the activity of a host of signaling molecules that alter gene expression and change the responsiveness (sensitize) of the central nervous system to subsequent input. Chronic painful stimulation may result in neurochemical changes (neuroplasticity) in the spinal cord such that all stimuli produce pain.(Gaynor 37)

Pain assessment in cats Currently the only validated acute pain scale for cats is the UNESP-Botucatu Multidimensional Composite Pain Scale .A shorter and easier to use pain scale is the Colorado State University Feline Acute Pain Scale. It involves a simple numeric scale with pictures outlining behavioural and psychological indicators of pain and includes response to palpation. This scale is not currently validated. For chronic pain, specifically related to degenerative joint disease (DJD) in cats, the only validated system is the NCSU Comparative Pain Research Lab’s Feline Musculoskeletal Pain Index. Behaviors evaluated include litterbox use, grooming, fluidity of gait, temperament, appetite, allowing petting and general activity. Use of activity monitors is another possibility to determine a cat’s pain. These have been used in scientific research and will have a place in feline pain determination in the future. No matter which system is used, results are best if the same person scores the cat’s pain each time to minimizer inter rater variability.

Pain management in cats Nonsteroidal anti-inflammatory drugs NSAIDs are one of the most common drug classes used to treat pain, and there is a robust body of information indicating that NSAIDs are effective in treating acute pain in cats.They have antipyretic, analgesic, and anti-inflammatory properties, which make them appealing therapeutic options; however, remember that there is not, and never will be, a completely safe NSAID for use in cats. ( lascelles) NSAIDs work to block the cyclooxygenase (COX) enzyme pathway to prevent production of eicosanoids and also work to inhibit central perception of pain. Eicosanoids are metabolically active compounds derived from 20-carbon fatty acids, usually arachidonic acid . The lipooxygenase ( 5-LOX) and cyclooxygenase (COX) enzymes are the rate-limiting steps in the production of leukotriene B4, thromboxane A2 and prostaglandin E2. The ideal NSAID should:  Spare COX-1 as much as possible ( to prevent GI erosion and renal tubular necrosis)  Inhibit COX-2 sufficiently for efficacy against pain and inflammation  Spare enough COX-2 to allow it to function in normal everyday processes

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Robenacoxib ( Onsior- Elanco) Robenacoxib is a targeted tissue selective and a unique COX-2 selective NSAID. It has a very short half-life (3 hours) in the blood, yet persists, and is active, for at least 24 hours in inflamed tissue in cats which demonstrates “tissue selectivity.” It is available in injectable and tablet form. Dosage: 1mg/kg q 24 hours Meloxicam ( Metacam—Boehringer Ingleheim) Meloxicam is a an example of a preferential COX-2 inhibitor that has greater inhibition of COX-2 than COX-1. It is also tissue selective but has a longer tissue half life than robenacoxib. Used for years in Canada, Europe and Japan. Has a black box label in the US because labelled dose is 0.3mg/kg once post surgery—too high a dose. Canada has a specific Metacam for Cats with a reduced dose—this dose seems to be the safest.Dose is Injectable 0.1mg/kg—once post surgery followed by oral dose of 0.05 mg/kg q 24 hrs for 5 to 11 days. Dose may be further reduced for long term therapy..we find 0.02mg/kg once daily as a good oral dose for cats with chronic pain—this is study supported although the study was not blinded.

Opiates Buprenorphine A partial mu-agonist that is used to manage chronic pain in cats and is classified by the Drug Enforcement Administration (DEA) as a Schedule III controlled substance. Buprenorphine is not approved by the Food & Drug Administration (FDA) for use in cats. The drug may be administered SC, IM, IV, or buccally; buccal administration is the preferred route for chronic pain management. Dosage: 0.01‒0.02 mg/ kg SC, IM, IV, or transmucosal. In July 2014, a new veterinary formulation of buprenorphine was FDA-approved and introduced into the marketplace (Simbadol, Abbott). At 1.8 mg/mL it is 6X more concentrated than the human commercial product Buprenex (0.3 mg/mL). It is labeled for post- surgical pain in cats, with a 24-hour duration with one injection at 0.24 mcg/kg subcutaneously (SC); it can be given daily for up to 3 days. The labeled dose is 0.24 mg/kg, approximately 10X the dose previously recommended. Shelf life 21 months unopened and 28 days opened. Tramadol—can be used but not approved, variable results in dogs but cats do make the M1 metabolite so better results in cats. In cats it is a mu agonist and serotonin–norepinephrine reuptake inhibitor. Cats are sensitive to the side effects of this drug and the bitter taste makes it difficult for cats to accept. Dose: 1-4 mg/kg q 8 to 12 hours Fentanyl—patch forms—variable efficacy

Analgesic adjuvants These are used in combination with NSAIDs or Opiates to treat chronic pain Amantadine Amantadine is an antiviral compound used in humans that is reported to exert an analgesic effect through NMDA receptor antagonism. Toxicity and kinetic studies have not been performed in cats. It is often effective however but can cause diarrhea in cats. Caution in cats with liver and kidney disease or seizures.Dosage: 3-5 mg/kg q 24 hours Gabapentin Gabapentin is an anticonvulsant that is used in cats for chronic pain particularly neuropathic pain. It is often used with amantadine and NSAIDs. It has been used to treat allodynia and hyperesthesia. Caution in cats with kidney disease—can be used at a reduced dose. Dosage: 5 to 10 mg/kg q 12 hours Amitriptyline Amitriptyline, a tricyclic antidepressant, is usually administered in combination with an NSAID for feline chronic pain of neuropathic origin.Avoid in seizuring animals or with liver disorders. Do not give along with Tramadol as you may cause serotonin syndrome. Dosage: 1-2 mg/kg q 12 to 24 hours

Nutraceuticals Adequan ( Polyglycoaminoglycan) and Cartrophen (Pentosan polysulphate) These injectables have been used in dogs and are also used in cats. The bioavailability and distribution of PSGAGs to inflamed joints in cats has been demonstrated with extralabel subcutaneous administration. Dosage: Cartrophen 1 ml per 33kg SQ once weekly for 4 weeks then once monthly Adequan: 5mg/kg once weekly x 4-6 weeks then q14d then once monthly ( SQ) Omega 3 fatty acids The primary source of omega 3 fatty acids is fish oil. A recent placebo controlled trial done with Royal Canin’s Feline Mobility support diet found significant improvement in indicators of pain and quality of life when comparing the base-line outcome measures to those collected at the end of the 16-week trial. ( Lascelles et al). Dose of combined EPA + DHA is maximum 100 mg/kg if using capsules or adding fish oil to the diet ( generally 1 tsp of fish oil is the maximum). There is a concern that this level of 606

supplementation may cause clotting problems in this species. However, research shows that at this level of supplementation, no cats experienced any clotting problems ( Joe Wakshlag, Cornell University, Personal communication) Green lipped perna mussel ( GLM) Perna canaliculus is found in the waters around Australia and New Zealand. It contains EPA, DHA, and ETA. It is also a source of glycoproteins and GAGs. The anti-inflammatory effects of GLM may be derived from its omega-3 fatty acids content or the GAGs or the glycoproteins. Suggested dose is 50-70mg/kg/d Herbals Flexadin Plus ( Vetoquinol) contains Devil’s Claw, Omega 3 and Glucosamine/chondroitin—seems to get a good rating but RCCT lacking. Avocado soybean unsaponifiables Avocado soybean unsaponifiables (ASU) are residues of avocado and soy oils combined in a 1:2 ratio to produce a product that has demonstrated anti-arthritic properties. Theoretically, ASU decrease the production of pro-inflammatory cytokines such as PGE-2 and TNF alpha. There are no published controlled trials in clinical cats with OA examining ASU alone or in combination products although in vitro studies have been conducted on feline chondrocytes.

Pain management beyond drugs Weight reduction Many cats with OA are overweight. As the OA worsens and becomes more painful the cats become less active contributing to an increase in weight. Excess weight causes an excess load on an abnormal joint, creating more pain. In addition the adipose tissue secretes adipokines which are pro-inflammatory and these increase the overall inflammation in the joint of the cat. Secret to weight loss in the cat is canned weight loss diet amount calculated by RER and exercise. Determine RER from Body Condition Score on a 9 scale. For every point that the cat is overweight over the ideal 5/9 body condition score, the cat is 10 % obese. For example a 10 kg cat with a body condition score of 7/9 is 2 x 10% or 20% over ideal weight. To determine Lean body weight in kilograms 10/1.20 = 8.3kg. Take this lean body mass of 8.3 and raise it to the 0.75 power. Multiply this result by 70 to give the RER. In this case a cat with a lean body mass of 8.3 kg has a RER of 342 kcal. Multiply this by 0.8 = 272 kcal..This is the number needed for weight loss. Use this formula and this calculation rather than amount on bag or can for weight loss. Exercise therapy can involve an obstacle course, playing with a feather, chasing a laser pointer, climbing a tower etc. A hockey rink with cat toys on a smooth surface can help with weight loss. Moving the food bowl during feeding and making the cat move around is helpful. Food balls can work for cats as well. Designing a cat tree so the cat has vertical and horizontal space is helpful. Indoor outdoor cats are thinner—cat gazebo is a possibility. Treadmill exercise can also be used for cats. Cat nip treats may entice cats to exercise. Acupuncture Acupuncture is a safe and often enjoyable method of pain relief for cats and should be considered as part of a multi modal pain management plan. It is minimally invasive and can be used with other modalities and medications as well. This author has used it in cat with back pain, osteoarthritis, stifle pain, post surgery, persistent pain post declaw, for excess grooming ( that was related to back pain) for interstitial cystitis and other conditions. There is a growing body of evidence for its use in veterinary medicine. Physical rehabilitation Physical rehabilitation is now considered a mainstay for pain relief post surgery and for geriatric animals. Cats are very amenable to all forms of physical therapies. Physical therapy should be considered part of a long term strategy for pain management in the cat. The goals of physical therapy are to restore muscular and joint strength and function, to restore balance and proprioception, to relieve pain, to improve mobility, endurance and flexibility. Physical rehabilitation can involve manual therapies, massage, laser therapy, hot and cold therapy, exercise therapy, joint mobilizations, ultrasound, electrical stimulation, myofascial release and hydrotherapy. Exercise therapies using balls, treadmills and other devices can be used with cats and often are simply limited by imagination. Passive range of motion (PROM) is a technique easily taught to clients to help relieve pain for stiff cats and one that should be employed for every geriatric cat.

References Bennett,D, Zainal -Ariffin, S and Johnson, P. Osteoarthritis in the Cat, Journal of Feline Medicine and Surgery (2012) 14, 76–84. KuKanich B. analgesia and pain assessment in veterinary research and clinical trials. Vet J 2011; 188 (1):1-2 Lascelles Bd, Robertson Sa, Taylor PM, et al. Comparison of the pharmacokinetics and thermal antinociceptive pharmacodynamics of 20 mcg/ kg buprenorphine administered sublingually or intravenously in cats. Vet Anaes Analges 2003; 30:109 (abstr). Lascelles BD, Henderson A, Hackett I. Evaluation of the clinical efficacy of meloxicam in cats with painful locomotor disorders. J Small Anim Pract 2001; 42:587-593. Pypendop B, Je i. Pharmacokinetics of tramadol, and its metabolite o-desmethyl-tramadol in cats. J Vet Pharmacol Ther 2007; 31:52-59.

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Sparkes AH, Heiene R, Lascelles BD, et al. isFM and aaFP Consensus guidelines, long-term use of Nsaids in Cats. J Feline Med Surg 2010; 12:521- 538. Tranquilli W, Grimm K, Lamont l. Pain Management for the Small Animal Practitioner, 2nd ed. Jackson, Wyoming: Teton New Media, 2004.

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Myofascial Pain: What’s All the Buzz? Janice Huntingford, DVM, DACVSMR, CVA, CCRT, CVPP, CAVCA Essex Animal Hospital Essex, Ontario

Myofascial Pain Syndrome( MPS) was brought to the attention of modern human medicine by Dr. Janet Travell in 1952 although it has been described in literature as long ago as the 16th century. Despite this, it has failed to enter mainstream medicine, especially in veterinary medicine. Many veterinarians do not even know of its existence! However, within the past decade this aspect of pain medicine along with many others has been steadily gaining a foothold in the general veterinary practice.

What is myofascial pain? The pathophysiology of myofascial pain is a complex syndrome involving in part, motor, sensory and autonomic nerve components. It is a myalgic condition in which muscle and tendon are the primary cause of pain. The syndrome is centered around the myofascial trigger point ( MTrP). A myofascial trigger point is an extended contraction of a few muscle fibers that results in a painful knot. Simons, Travell and Simons define it as “ a hyper irritable spot in skeletal muscle that is associated with a hypersensitive palpable nodule in a taut band. The spot is tender when pressed and can give rise to characteristic referred pain, motor dysfunction and autonomic phenomena.”1 Therefore all MTrPs have a sensory component, a motor component and an autonomic component. When the motor end plate is overstretched which can happen when only a few muscle fibers are activated then myofascial tension is increased in that fiber. An increase of tension of only 1% will evoke a 10 % increase in ACh release. With excessive release of ACh there is excessive motor activity. The local muscle contraction compresses local sensory nerves and blood vessels and reduces the supply of oxygen to the area. Decreased oxygen and increased metabolic demands of the contracted muscle fibers result in a depletion of the local ATP. This cause pre and post synaptic changes in the Calcium pump and leads to muscle spasms. Trigger points are formed which are painful and either excite or inhibit activity on motor activity in the muscle or its functionally related group. This inhibition causes poor co- ordination and muscle imbalances. There are also autonomic phenomena associated with MTrPs.2

Etiology of MTrPs Mechanical issues Acute trauma may activate MTrPs but does not perpetuate them. Sudden activation can occur with direct trauma, muscle strain, joint sprain or excessive or unusual exercise. Mostly commonly are formed with chronic muscle overload such as occurs with orthopedic injury, neuropathy, joint dysfunction or osteoarthritic pain. It is thought that low level muscle contractions, unaccustomed eccentric contractions or eccentric contractions isn unconditioned muscle as well as maximal or sub maximal concentric contractions may lead to MTrP formation. In OA the joint dysfuntion and postural changes can activate and perpetuate MTrPs. With coxofemoral arthritis the muscles that frequently develop trigger points are the sartorius, tensor fascia lata, pectineus, rectus femoris and iliopsoas ( hip flexors). Due to the forward weight shift , they also develop in the triceps, infraspinatus and deltoid muscles. Because pelvic movement is compromised, and more lateral flexion of the spine occurs, the iliocostalis lumborum and lateral multifidi are also effected. If a dog is hopping on one back leg, trigger points can develop in the contralateral limb and hopping causes excessive eccentric contraction of the stifle extensors. In this leg we see MTrPs in the sartorius, tensor fascia latae, rectus femoris and vastus group. The lumbar paraspinals are also involved as they assist in ambulation.4 Nutritional deficiencies and metabolic issues3 It is unknown if nutritional deficiencies or metabolic problems perpetuate trigger points in dogs but in humans they have been linked with certain deficiencies such as cobalamin, folate, iron deficiency, Vitamin D and B12 deficiency and metabolic diseases such as hypothyroidism and diabetes. Examination techniques3 MTrPs are diagnosed by palpation. 3 types of palpation are used: Flat palpation, Pincer Palpation and Snapping palpation. With flat palpation the finger pressure is applied at right angles to the muscle fiber compressing against the bone—this is used for the infraspinatus, supraspinatus and psoas muscle. With Pincer Palpation the muscle bands are pinched and rolled between thumb and fingers to detect taut bands. This works for the triceps, sartorial and tensor fascia latae. Snapping palpation is similar to pincer but the fibers are rolled under the finger similar to plucking a guitar string. Taut bands are palpated and usually animal is painful so jumps ( Jump sign)

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Clinical cases Brooklyn the Rottweiler F/S 5 year old Rottweiler BCS 6/9, had TPLO LH 1 year ago and still not using leg well. Current pain medications included Meloxicam and Tramadol. On examination she had a large number of MTrPs in her iliopsoas, sartorial, TFL on the left side and Triceps bilaterally. All of her hip flexors were sore to the point she resent extension of her stifle and was vocal and aggressive with the iliopsoas test. Because Brooklyn had spent a lot of time with her leg contracted she had slight muscle contractions of the hip flexors due. The front leg MTrPs were due to compensation from weight shifting. Brooklyn was uncomfortable and her owners were frustrated. Treatment: Sedation and dry needling After one session Brooklyn was more comfortable and would allow her muscles to be touched. A rehabilitation program including acupuncture, UWTM, stretching, leg and core strengthening was able to proceed. Within 1 month Brooklyn was back to her normal self and was fully weight bearing. Regi the wirehaired fox terrier Regi, 11 yr old F/S BCS 6/9 former agility dog, pain in sacral area, elbow arthritis, lagging in walks and not wanting to go many places. Owner felt she was depressed. She noticed Regi was walking “funny” in the front end and base wide in the hind end. She had had several rehabilitation sessions for strengthening and gait retraining as well as medication—Gabapentin, Amantadine, Chinese herbs, acupuncture—nothing seemed to be helping. My examination revealed myofascial pain in her iliopsoas, quadriceps, and sartorial and in the triceps and infraspinatus muscles of both front legs. Treatment: Sedation and dry needling Result: Regi continued rehab therapy but this time there was a big improvement. She went back to walking well and was no longer depressed. Dry needling is the preferred method of treatment in myofascial pain syndrome in dogs. Dry needling involves the act of placing an acupuncture needle directly into the painful trigger point resulting in a complex cascade of events involving in part spinal reflexes, increased blood flow and an increase in the amount of energy available to the muscle. This causes the taut band of muscle containing the trigger point to relax and the pain relief is immediate. When Brooklyn’s owner picked up her dog after the first session, she was misty-eyed with relief when she saw Brooklyn walking normally as she came out to greet her. Dry needling imparts an immediate benefit but it generally requires several sessions to give complete relief. And unless the underlying cause can be found and completely treated, it eventually returns needing additional treatments, especially in the case of chronic conditions like osteoarthritis. Dry needling is not taught in university settings. The only regular classes that a veterinarian can take is through the Canine Trigger Point Therapy Program given through Myopain Seminars and taught by Drs. Jan Dommerholt and Rick Wall.4

References 1. Travell JG, Rinzler SH. The myofascial genesis of pain. Postgrad Med 1952;11:452-434. 2. Treaster D, Marras WS, Burr D, Sheedy JE, Hart D. Myofascial trigger point development from visual and postural stressors during computer work. J Electromyogr Kinesiol 2006;16:115-124. 3.Dommerholt, J, and Huijbregts, P. Myofascial Trigger Points: Pathophysiology and Evidence-Informed Diagnosis and Management. Sudbury, MA. Jones and Bartlett, 2011 4.Wall, Rick. Myopain Seminar Course Notes, Canine Trigger Point Course, www.myopainseminars.com

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Nutraceuticals for Pain Janice Huntingford, DVM, DACVSMR, CVA, CCRT, CVPP, CAVCA Essex Animal Hospital Essex, Ontario

What is a nutraceutical? A food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease.

What is a dietary supplement? Product taken by mouth that contains a dietary ingredient intended to supplement the diet or a substance produced in purified or extracted form which, when administered orally to patients, aims to provide them the necessary elements for their structure and normal function to better their health and wellbeing. Nutraceuticals are used by a large number of veterinary clients for osteoarthritis and are one of the fastest growing areas of supplementation for pets.

Normal joint structure and function The ECM of articular cartilage is mostly protein and water and has both interfibrillar ( ground substance) and fibrillar components. The fibrillar component is composed of mostly collagen and elastin. Collagen is the most abundant protein in the body, has a tensile strength similar to steel, is responsible for the integrity of the tissues and their resistance to tensile forces. The interfibrillar component is mostly glycoproteins and proteoglycans (PGs) Proteoglycans provide the articular cartilage with selective permeability properties and compressive stiffness, while the collagen fibers provide tensile strength. Proteoglycans have a negative charge & great affinity for water and have the potential to absorb 50 times their weight in water. However, the collagen framework in normal cartilage constrains the proteoglycans and limits their ability to expand to about 20% of their potential. This swelling pressure keeps the cartilage turgid, helping to resist deformation when a compressive load is applied. This dynamic tissue is able to tolerate both compressive and shearing forces without damage, transmitting and distributing the forces to the underlying subchondral bone, which aids in shock absorption. The proteoglycans in articular cartilage are large aggregates of protein, hyaluronic acid and glycosaminoglycans, predominantly chondroitin 4-sulfate, chondroitin 6-sulfate, and keratan sulfate. Glycosaminoglycans (GAGs) are long unbranched polysaccharides consisting of a repeating disaccharide unit. This unit consists of an N-acetyl-hexosamine and a hexose or hexuronic acid, either or both of which may be sulfated. The combination of the sulfate group and the carboxylate groups of the uronic acid residues gives them a very high density of negative charge. Members of the glycosaminoglycan family vary in the type of hexosamine, hexose or hexuronic acid unit they contain (e.g. glucuronic acid, iduronic acid, galactose, galactosamine, glucosamine). They also vary in the geometry of the glycosidic linkage (N or O linkage) GAG chains covalently linked to a protein to form proteoglycans. Extensive notes on the pathogenesis of osteoarthritis have been provided for a previous lecture but to review the pathogenesis of osteoarthritits on a cellular level, stresses on the joint lead to production of inflammatory cytokines released by synovial cells, chondrocytes, macrophages and fibroblasts. These proinflammatory cytokines, including certain interleukins and TNF-alpha, lead to upregulation of COX-2 enzymes and production of eicosanoids such as PGE2,and the upregulation of matrix metalloproteinases. Normally during metabolism PGs are broken down by enzymes matrix metalloproteinases ( MMPs) and aggrecanase. In acute inflammation MMPs increase in number and disrupt the balance of production and destruction in the joint. There is shift toward breakdown of articular cartilage resulting from an imbalance between MMPs and their TIMP inhibitors, leading to thinning and destruction of the cartilage tissue and perpetuation of the inflammatory cascade with PGE2 production and subsequent pain. On a gross level, the thinning or loss of cartilage leads to joint space narrowing, remodelling of subchondral bone with sclerosis and osteophyte formation, joint effusion, periarticular swelling and pain which may lead to decreased use of the joint and secondary atrophy of musculature.

Goals for a nutraceutical to relieve OA pain 1. Decrease in inflammatory prostaglandin (PGE2). 2. Decrease the production of Pro MMP 2 & 9 and active MMP 2 and 9 ( the enzymes responsible for degradation of cartilage. 3. Increase the inhibitor of MMP (TIMP-2) to help restore proper balance between these enzymes.

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Evidence based nutraceutical use Fish oil--Omega 3 DHA and EPA1,2,3,4 Arachidonic acid (AA) is the primary substrate for the lipooxygenase and cyclooxygenase enzymes. This fatty acid is derived from dietary sources and stored in phospholipids of the cell membrane until needed. AA is a member of the omega-6 fatty acid family. AA can be partly replaced in cell membranes by the omega-3 fatty acid Eicosapentanoic Acid. The difference between omega-6 and omega-3 fatty acids centers on the location of the first double bond in the carbon chain, occurring either at the 3rd or 6th carbon from the methyl end. While mammalian cells can elongate and desaturate fatty acids, they are not able to form double-bonds beyond these defining bonds, so are unable to synthesize these fatty acids nor interconvert between these families. Thus, the presence of these fatty acids within cell membranes reflects dietary intake. And this can be important because the physiologic function of the 2 fatty acid families differ. Eicosanoids are metabolically active compounds derived from 20-carbon fatty acids, usually arachidonic acid . The lipooxygenase ( 5-LOX) and cyclooxygenase (COX) enzymes are the rate-limiting steps in the production of leukotriene B4, thromboxane A2 and prostaglandin E2. In health, these eicosanoids serve important functions. However, in inflammatory conditions such as arthritis, their production can be increased and their effects can be detrimental. For example, PGE2 can be increased up to 50 fold in arthritic joints. Leukotriene B4 has a potent chemotactic effect and promotes further inflammation. PGE2 and TXA2 both promote the release of tumor necrosis factor alpha and Interleukin 1beta, both which promote further inflammation and, in joints, stimulate the production of matrix metalloproteinases or MMPs. MMPs are the collagen-destroying enzymes that break down articular cartilage in arthritic joints. Further, PGE2 is a potent stimulator of pain receptors, and contributes to the pain of arthritis. Eicospentaenoic acid (EPA) also can be used by the LOX and COX enzymes to produce eicosanoids. However, when EPA is used by the COX and LOX enzymes, they produce the eicosanoids PGE3, thromboxane (TX) A3 and LTB5, which are less active and relatively anti-inflammatory compared to their counterparts produced from AA. It has been demonstrated that therapeutic diets containing approximately 3.5% omega 3 fatty acids can decrease pain and lameness, improve weight bearing, and decrease the need for NSAIDs in dogs with OA. The primary source of omega 3 fatty acids is fish oil. Approximately 480 mg/kg of fish oil (50‒100 mg/kg EPA) would be required as a supplement to match the amounts available in the therapeutic food discussed above. A recent placebo-controlled clinical trial in dogs with OA investigated the effects of a fish oil supplement added to a non-fish based food, dosed at 90 mg/kg EPA and 20 mg/kg DHA. These researchers found significant improvement in indicators of pain and quality of life when comparing the base-line outcome measures to those collected at the end of the 16-week trial. There is a high level of support for supplementation of omega 3 fatty acids. Mobility diets All mobility diets are not created equal! Research shows that 7.5 g EPA +DHA/1000kcal diet significantly reduced symptoms of arthritis. This amount is quite unwieldy as well as likely to cause diarrhea. Other studies have shown as little as 1 to 3 g/1000kcal has clinical effect. Ideally for most dogs you would like to get up to the 100mg/kg of Omega 3 for arthritis. Here is an example: For a 20kg dog you would like it to receive 2 g of Omega 3 total/day for arthritis. This dog would eat around 700 kcal so if feeding a 1.5 g Omega 3/1000kcal diet it would provide approximately 1 gram of Omega 3. To make up the additional gram, you would have to supplement with 2 capsules that contain 500mg of EPA and DHA combined. This is quite feasible. Green-lipped mussel Perna canaliculus is found in the waters around Australia and New Zealand. It contains EPA, DHA, and ETA. It is also a source of glycoproteins and GAGs. A randomized, double- blind, placebo controlled clinical trial in dogs with chronic pain attributed to OA found significant improvement in mobility and pain in those dogs treated with GLM compared to placebo. The dose used was 50 mg/kg. The anti-inflammatory effects of GLM may be derived from its omega-3 fatty acids content or the GAGs or the glycoproteins. This has yet to be determined but it does prove to be at least mildly effective.6,7 Avocado/soybean unsaponifiables Avocado soybean unsaponifiables (ASU) are residues of avocado and soy oils combined in a 1:2 ratio to produce a product that has demonstrated anti-arthritic properties. Theoretically, ASU decrease the production of pro-inflammatory cytokines such as PGE-2 and TNF alpha. In a canine cruciate ligament transection model, ASU administration decreased osteophytes, improved cartilage thickness and produced more normal chondrocytes. 11 Additional in vitro studies have shown that the combination of ASU with chondroitin is more effective in decreasing inflammatory cytokines than either product alone. There are no published controlled trials in clinical dogs with OA examining ASU alone or in combination products. However research on induced arthritis shows a positive result. Dasuquin ( Nutramaxx) is the product generally used.

Chondroprotectants Glucosamine/chondroitin5 Glucosamine is a precursor of glycosaminoglycan (GAG). When administered orally, glucosamine is 90% absorbed and undergoes biotransformation in the liver. It is then distributed to tissues and has been shown to have a tropism for articular cartilage. Glucosamine sulfate is absorbed better than glucosamine hydrochloride and may be more effective. 612

The mechanism of action of glucosamine has not been fully elucidated. In vitro studies have shown that when exogenous glucosamine is administered, it is utilized in the synthesis of GAGs. It has also been demonstrated that supplementation with glucosamine inhibits enzymes that are responsible for the degradation of cartilage, and the production of inflammatory mediators is decreased. Chondroitin sulfate is a much larger molecule than glucosamine, and its oral bioavailability has been questioned. Low-molecular weight chondroitin sulfate is more effectively absorbed by the gastrointestinal tract than larger molecules. Metabolites of chondroitin sulfate are concentrated in articular cartilage.The mechanisms of action of chondroitin are: to stimulate GAG production; inhibit degradative enzymes; enhances the production of hyaluronic acid and prevent the degeneration of type II collagen within articular cartilage. Glucosamine and chondroitin sulfate are often combined in commercially available products. It appears that there is a synergistic effect when the two products are used together. Studies demonstrating efficacious use of glucosamine/ chondroitin are few. McCarthy et al showed glucosamine/ chondroitin improved pain, weight bearing and disease severity scores (3/5 measures) but the onset of response was slower for glucosamine/chondroitin compared to NSAIDs. 5Moreau et al showed no change with the supplement so evidence is conflicting.12 In a systematic review only 13 studies were controlled and evidence was positive for Glucosamine/chondroitin but this is a human study.The level of evidence supporting the use of glucosamine/chondroitin for pain management in dogs is low. Dosage: Dose at 15mg/kg on the Chondroitin fraction. Adequan Polysulfated glycosaminoglycans (PSGAGs) are a semisynthetic product (derived from bovine trachea) structurally similar to the GAGs found in articular hyaline cartilage. PSGAGs stimulate collagen synthesis and inhibit collagen breakdown as well as decrease pain and inflammation. Several studies have documented positive effects when administering PSGAGs (Adequan) to dogs with hip dysplasia and osteoarthritis. One study found decreased hip laxity in dogs treated with Adequan twice weekly from 6 weeks to 8 months of age compared to age-matched controls. It is recommended to begin treatment as early in the disease process as possible in order to slow the progression of cartilage damage. The strength of evidence for PSGAGs used at the labeled dose is considered high. Dose: 5mg/kg once weekly x 4 to 6 weeks then once monthly in dogs, cats first 4 weeks is the same but 2nd month every other week then once monthly10 Cartrophen Pentosan polysulphate—this product is used in Canada, Europe and Australia. Similar actions to Adequate. Dose is 1ml/33kg once weekly for 4 weeks then once monthly.

Herbals and natural supplements Flex-RX This product is a bioflavanoid that contains Baicailin and Catechin and has balanced COX and 5-LOX enzyme inhibition activity. In studies by Burnett et al it showed statistically significant improvement in pain scores when compared to Cosequin using veterinarian and owner VAS. Elk velvet antler Quality Elk Velvet comes from the antler at the velvet stage and contains Chondroitin Sulphate, collagen, glycosaminoglycan and pilose antler peptide. Study by Morneau showed improvement in dogs with clinical OA on force plate and by subjective analysis.12 Boswellia This is also know as Indian Frankincense in Ayurvedic Medicine. 4 compounds isolated have been isolated and purified. These have been found to have anti-LOX activity. This herb is found in human products Flexamine as Aflapin and Osteo-biflex as 5-Loxin. 2 Placebo controlled clinical trials in humans suggest efficacy for joint pain. In an unblinded open label Austrian study it was found to have 71 percent positive response in clinically lame dogs.9,8 Theracurmin Curcumin is found in veterinary nutraceuticals marketed for arthritis. Its utility as a natural NF- kB (nuclear factor kappa-light-chain- enhancer of activated B cells) and cyclooxygenase-2 inhibitor is documented in humans but not in dogs. However, its gastrointestinal absorption in most species appears to be poor. An extract of turmeric, the spice from which curcumin is derived, produced subjective, but not objective, improvements in dogs with arthritis. Theracurmin is a new water soluble curcumin that has shown to have advantages and may have promise in the future in dogs.

References 1. Fritsch D, Allen TA, Dodd CE, et al. Dose-titration effects of fish oil in osteoarthritic dogs. J Vet Intern Med 2010; 24:1020-1026. 2. Fritsch DA, Allen TA, Dodd CE, et al. A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. JAVMA 2010; 236:535-539. 3. Roush JK, Cross AR, Renberg WC, et al. Evaluation of the effects of dietary supplementation with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. JAVMA 2010; 236:67- 73. 613

4. Hannah SS, Laflamme DP. Increased dietary protein spares lean body mass during weight loss in dogs. J Vet Intern Med 1998; 12:224. 5. Vandeweerd JM, Coisnon C, Clegg P, et al. Systematic review of efficacy of nutraceuticals to alleviate clinical signs of osteoarthritis. J Vet Intern Med 2012; 26:448-456 6. Rialland P, Bichot S, Lussier B, et al. Effect of a diet enriched with green-lipped mussel on pain behavior and functioning in dogs with clinical osteoarthritis. Can J Vet Res 2013; 77:66-74. 7. Pollard B, Guilford WG, Ankenbauer-Perkins KL, et al. Clinical efficacy and tolerance of an extract of green-lipped mussel (Perna canaliculus) in dogs presumptively diagnosed with degenerative joint disease. N Z Vet J 2006; 54:114-118. 8. Hamidpour R, Hamidpour S, Hamidpour M, et al. Frankincense (Ru Xiang; species): From the selection of traditional applications to the novel phytotherapy for the prevention and treatment of serious diseases. J Trad Complement Med 2013; 3:221-226. 9. Reichling J, Schmokel H, Fitzi J, et al. Dietary support with Boswellia resin in canine inflammatory joint and spinal disease. Schweiz Arch Tierheilkd 2004; 146:71-79. 10. Oke SL. Indications and contraindications for the use of orally administered joint health products in dogs and cats. JAVMA 2009; 234(11):1393- 1397. 11. Boileau C, Martel-Pelletier J, Caron J, et al. Protective effects of total fraction of avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: Inhibition of nitric oxide synthase and matrix metalloproteinase-13. Arth Res Ther 2009; 11:R41. 12. Moreau M, Dupuis J, Bonneau NH, Lecuyer M. Clinical evaluation of a powder of quality elk velvet antler for the treatment of osteoarthrosis in dogs. Can Vet J 2004; 45(2):133-139.

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Poop in the Coop: What it Tells You about Backyard Chicken Parasites Richard Gerhold, DVM, MS, PhD University of Tennessee Knoxville, TN

Avian parasites consist of multiple species including helminthes, protozoa and arthropods. Included are some of the important parasites that may be found in various avian species. The likely hood of infection will depend if the birds are pet birds, captive collection, or backyard species. The listed parasites in this paper are not inclusive but give the major pathogenic producing parasites that may be encounter in veterinary medicine. Toxoplasma gondii causes toxoplasmosis which is infectious for all birds. Cats are the definitive host and shed oocysts in their feces. Clinical signs in affected birds include incoordination, listlessness, seizures, and convulsions. Lesions can range from encephalitis, myocarditis, pneumonia, and splenomegaly. Infected birds can be diagnosed using the modified agglutination test Necropsy findings include histopath examination and PCR on affected tissues can identify T. gondii as well. Limiting cat access to yard is the most effective prevention and owners should be strongly encouraged to keep cats indoors. Baylisascaris procyonis is a roundworm of raccoons and birds are infected by ingesting larvated eggs in the environment. Dogs can also serve as the definite host for B. procyonis and can shed eggs. The distribution of B. procyonis has been increasing recently. Larval migrans of B. procyonis can result in numerous neurological impairment clinical signs including encephalitis, circling, seizures, and death. Necropsy diagnostics include histopath examination and PCR. Limiting raccoon access to yard and making the areas unattractive to raccoons is the main way to prevent this disease. Oxyspirura sp. roundworms which lead to eye worm infection have been reported in avian families. Affected birds generally have swollen conjunctiva and birds are observed scratching their eyes. The globe can be rendered non function from chronic inflammation. Infection in birds occurs by eating infected cockroaches so limiting arthropod ingestion is important. Ivermectin has been useful in treatment of eyeworms. Avian trichomonosis is caused by Trichomonas gallinae which is a protozoal parasite that primarily affects columbids, birds of prey, turkeys and passerines. Clinical signs include swollen crop, listlessness, ruffled feathers, and often open mouthed breathing. Variable lesions can consist of caseous necrosis within the oral cavity and esophagus and less frequently the liver. The presence of the parasite does not indicate disease given the wide spectrum of virulence. Transmission of the parasite occurs by direct avian contact or via contaminated food and water. Gross lesions of trichomonosis are not pathognomonic. Other diseases including avian pox, candidiasis, aspergillosis, oral Capillaria spp. infection, and vitamin A deficiency can have similar gross findings. Testing to confirm infection is conducted by examining the oral swabs via wet mount by light microscopy to observe the undulating swimming motion. PCR testing is available as well. Successful treatments in early infections include metronidazole and carnidazole. The thread-like nematode, Capillaria contorta can be found in the oral cavity and esophagus of numerous various avian species. The parasites are slender and long and may be difficult to see grossly. Lesions are similar to T. gallinae infection. Birds are infected by ingesting extremely environmentally resistant eggs and as such, treatment without prevention will not stop infection in a flock. Other capillarid spp. can be found in the gastrointestinal tract leading to weight loss. Syngamus trachea often referred to as the gape worm often leads to open mouth breathing due to parasite infection of trachea. The parasites are red color and form a “Y” shape in the trachea. Variable clinical signs can include gaping and gasping, listlessness, and lethargy. Infected birds can be treated with benzimidazole antihelmentics. Coccidiosis is an important disease in captive birds. Oocysts are shed in the host’s feces and following ingestion by another host, lead to cellular infection. Anticoccidial compounds fall into two categories including polyether ionophores and enzymatic reaction compounds. Ionophore compounds allow limited cycling of the coccidia in the bird which aids in producing immunity. Variable compounds are available and depending on previous compound use on a particular farm, experimentation may be needed to determine useable compound. Maxiban (narasin/nicarbazin) is toxic in turkeys. Live vaccines are available for use in the poultry industry; immunity develops rapidly after exposure, but needs reinfection to reinforce the developing protection. The protozoa Histomonas meleagridis is the cause of blackhead and is considered the most important parasitic disease for wild turkeys and is an important cause of mortality for numerous game birds and domestic turkeys. Recently mortality has been seen in backyard chickens. Clinical signs include yellow diarrhea, weight loss, and ruffled feathers. Lesions include target shaped necrotic areas in the liver and ceca are markedly thickened with necrotic material. On fresh carcasses, histomonads can be observed via wet mounts of swabs from affected organs. Ring-neck pheasants are the natural host for H. meleagridis however chickens can serve as unapparent carrier for the parasites including the Heterakis nematode that is a vector for Histomonas. For this reason, turkeys, quail, grouse, or chukars cannot be raised in the same areas as chickens or pheasants. Nitrasone (Histostat7 Alpharma Inc. Clifton, New Jersey) has been used to prevent outbreaks; however, this drug is now banned,

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Ascardia spp are frequently reported in birds and can interfere with intestinal passage of food. Ascarids are relatively large and range from 3-6 cm in length in comparison to Heterakis spp. ranging from 0.5-1.0 cm.

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Worm in the Brain: Update on Meningeal Worm Infection in Goats, Sheep, and Camelids Richard Gerhold, DVM, MS, PhD University of Tennessee Knoxville, TN

Meningeal worm or brain worm infection in camelids, elk, moose, and sheep and goats is caused by the roundworm parasite, Parelaphostrongylus tenuis. Meningeal worm infection is one of the most common causes of neurological illness and death in camelids and treatment of chronic cases are often difficult and expensive. Infected animals present with a head tilt, arching of the neck, incoordination, difficulty getting up, and/or gradual weight loss. The parasite causes disease by migration of the worm through the brain or spinal cord of affected animals leading to internal trauma and inflammation. Currently, no live animal test is available and post-mortem testing is performed by microscopic examination of brain sections for evidence of the worm migration pathways. Aberrant migration of meningeal worm larvae through the neuropil and spinal cord of camelids, especially alpacas and llamas, causes severe clinical neurological disorders. Camelids are exposed to the intermediate larval stages of P. tenuis via the accidental ingestion of infected terrestrial slugs and snails. Many other domesticated species have also been proven to be susceptible to P. tenuis infection including sheep, horses, cattle, and bison. Infected animals present with a head tilt, arching of the neck, incoordination, difficulty getting up, and/or gradual weight loss. Treatment for camelids and ungulates with moderate to severe clinical disease is often expensive, but unrewarding, despite use of numerous anthelmintics and supportive. Parelaphostrongylus tenuis infection also has a huge impact on wildlife conservation. The natural host of the metastrongylid parasite is the white-tailed deer, Odocoileus viginianus, which are unapparent carriers of the parasite. However, in other species of ungulates, like those listed above, the response to infection is quite different. The larvae emerge from accidentally ingested slugs and snails, and penetrate the host’s gastrointestinal track. From there, they migrate to and develop within the spinal cord for up to 1 month. The migrating P. tenuis larvae cause extensive central nervous system (CNS) damage and disabling neurologic disease. Lesions caused by P. tenuis migration are often difficult to identify, due to the fact that their histologic appearance varies so greatly. Currently, there is no commercially available antemortem test to confirm Parelaphostrongylus spp. infection in any species. Suspect cases of P. tenuis is often made in camelids following detection of cerebrospinal fluid (CSF) eosinophilic inflammation, combined with the clinical signs of head tilt, arching of the neck, incoordination, difficulty getting up, and/or gradual weight loss. A nested PCR can be used to detect P. tenuis from formalin fixed tissue which was successfully used for detection of Parelaphostrongylus spp. DNA in a Sika deer, horse, cattle, and guinea pig. Prevention of parasite infection include minimizing deer populations through hunting, high fences to exclude deer, the use of livestock guardian dogs, and use of rock lined area on the outside of the fence. The use of molluscicides on the outer fence rocks can impede the entry of infected gastropods into pastures and minimize infection of P. tenuis into camelids and other animals. The use of injectable ivermectin has been used to prevent infection in P. tenuis infection; however, unintentional side effects could be selection of ivermectin-resistant Haemonchus contortus and other gastrointestinal nematodes. Treatment for cases of meningeal worm include febendazole and anti-inflammatory drugs, particularly in early stage infections. As disease progresses, prognosis is less favorable and treatment may require a sling or further assistance given at a referral clinic.

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How to Identify and Treat Toxoplasma, Isopora, and Other Coccidial Infections Richard Gerhold, DVM, MS, PhD University of Tennessee Knoxville, TN

Eimeria spp. have a direct life cycle and ingested sporulated oocyst reproduce in respective organs including liver, kidney, and mainly intestines. Through the process of multiple rounds of asexual reproduction will produce large number of merozoites. Following the last round of merizoite replication, the merizoites will differentiate into male and female stages to begin sexual reproduction. Once fertilization occurs feces. The processes of both asexual and sexual reproduction result in rupture of the infected cells and associated disease as a result of epithelial destruction. The life cycle of Atoxoplasma, a coccidian parasite that infects birds, also has a direct life cycle with both asexual and sexual life stages. The asexual reproduction occurs in the intestines of infected birds and also in mononuclear phagocytes of the gut mucosa, resulting in infected mononuclear cells containing the merozoite that may stay in the gut or enter the blood to disseminate the parasite to other extraintestinal tissues such as the liver. Sexual reproduction occurs in the intestines and results in the excretion of oocysts in the feces. Toxoplasma gondii and Isospora are different in that they have a direct life cycle but can utilize a paratenic host. The only definitive host for Toxoplasma is the cat. Thus, sexual reproduction (the formation of micro and macrogamonts) and shedding of oocysts occurs only the gastrointestinal tract of felids. Oocysts that are shed in the feces of cats will sporulate to become infective to nearly any warm-blooded vertebrate host. Any warm-blooded animal that consumes the oocyst may act as a paratenic host – i.e., the parasite can live in the tissues of the paratenic host but the parasite does not require growth or multiplication in the paratenic host in order to complete its life cycle. When the cat or paratenic host ingests the infective oocyst, the sporozoites are released and undergo massive asexual reproduction in the cells of the intestines and lymph nodes producing tachyzoites. These tachyzoites continue to multiply in other cells of the body (extraintestinal phase); destruction of infected cells is what results in disease and signs of disease will depend upon the organ infected (i.e., pneumonia if damage occurs in lungs, neurologic signs if damage occurs in brain). After the fast replicating tachyzoite stage, a slow replicating bradyzoite stage will begin in which the parasite forms cysts, containing the bradyzoites, in various tissues that can include the brain. The cysts will persist for the life of the animal. If a cat ingests a parentic host that has the encysted bradyzoites, the bradyzoites will enter the small intestinal epitheial cells and first undergo asexual reproduction and then the sexual reproductive life stage, shedding oocysts 3-10 days later. If the life cycle is direct, and the cat ingests sporulated oocysts (rather than the encysted bradyzoites of a paratenic host), it take 19-48 days to shed oocysts which suggests that the parasite can accomplish much of the required asexual reproductive stages in the process of forming bradyzoites in the paratenic host. Isospora may undergo direct transmission or indirect transmission by use of a paratenic host. A rodent or bird may act as a paratenic host by ingesting the sporulated oocyst. In the paratenic host, the sporozoite is released from the oocyst and migrates to lymph nodes where it will encyst (monozoic cyst) and be infective to the carnivore that consumes the rodent. The host may consume the infected paratenic host or ingest the sporulated oocysts from the environment. There is no extraintestinal life cycle for this coccidian and both asexual and sexual reproduction occurs in the villar epithelium and nonsporulated oocysts are excreted in the feces. However, extraintestinal migration of the parasite may occur in the host after ingestion of the sporozoites in the host. Some sporozoites may enter the mesenteric lymph node (as also seen in the paratenic hosts) or may enter other extraintestinal tissues (spleen, liver) where they form cysts. Thus, monozoic cysts may form in both the definitive and paratenic hosts and remain for the life of the animal. In definitive hosts, the cyst may rupture and release sporozoites to reinfect the intestine. The advantage of having an asexual life stage for these coccidian parasites is the ability for the parasite to rapidly and markedly increase the number of parasites from the ingestion of only a single sporozoite. Asexual reproduction allows the parasite to quickly and exponentially increase in a non-immune host. In theory one ingested oocyst can produce close to a 1million new oocysts in feces of naïve animal depending on age and available intestinal cells to infect. Most (although not all) coccidian parasites undergo sexual reproduction in the gut. This is an important strategy for transmission because oocysts are therefore shed in the feces for a feco-oral transmission. Infection can result in clinical signs as a result of cellular destruction (the severity of disease seen is related to the degree of infection and cellular destruction). Diarrhea will increase the environmental contamination, which can aid in transmission especially in a captive environment. Although coccidiosis may cause morbidity and/or mortality, it would not be advantageous to the parasite to cause high degree of mortality thus the asexual reproduction ceases after a genetically predetermined number of cycles (which may vary per coccidian species). Parasitic encystment (either as encysted bradyzoites in Toxoplasma or as monozoic cysts in the paratenic or definitive hosts for Isospora) is another strategy for the parasite for transmission or reinfection. The use of a paratenic host by Isospora and Toxoplasma is an advantageous because it increases the chance of exposure to the definitive host by “presenting” the parasite back to the definitive host. By infecting prey species (and affecting the prey species such that it is more susceptible to predation as is seen in Toxoplasma

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infection of rodents) the parasite increases its chances of returning to the felid host to complete the sexual stage of the life cycle. For wild felids with large home-ranges and solitary behavior, the ingestion of a paratenic host may be more likely than ingestion of infective oocysts directly. Many, if not all, animals have been reported with one or more coccidian parasites, but infection does not typically cause disease in free-ranging wild animals in natural conditions. Clinical coccidiosis is seen in captive animals because transmission is enhanced by captive conditions. Because there is no requirement for an intermediate host, these parasites with a direct life cycle are easily transmitted in captive environments. Environmental contamination in a closed/confined space is much greater than over a natural habitat and the controlled temperature and humidity of captive animal holding can promote sporulation of the oocyst to its infective form. The oocysts can be destroyed by desiccation and direct sunlight but many commonly used disinfectants are not effective and thus a captive environment can be easily contaminated. Captive animals are also typically found at much higher density than wild animals, increasing the chance for shedding and exposure. In breeding or production facilities there are young animals that have not yet developed immunity to the parasite and are susceptible to infection clinical disease and likely to shed the parasite. Coccidian oocysts may be shed from asymptomatic animals as well (there have been reports of 30-50% prevalence in apparently healthy animals of a range of species) thus environmental contamination and risk for reinfection is high in a captive environment. Lastly, stress is a known factor in the development of clinical coccidiosis. “Winter coccidiosis” in cattle occurs likely due to the stress of extreme temperatures in combination with infection, while outbreaks of clinical coccidiosis have been seen after shipping (another stressful event) in other species. Sources of stress in captive animals can include high stocking density, poor nutrition, competition, and handling that could contribute to the development of clinical coccidiosis. While wild animals also have stressors, they do not have the added combination of high levels of environmental contamination, high stocking density, and intensive breeding or production. The most pathogenic lesions in enteric coccidiosis occur as a result of the host cell rupture during the asexual propagation. Most coccidia develop in villus enterocytes but others may develop in crypt enterocytes or lamina propria. Rupture of the host cell at the end of merogony is associated with the release of schizonts (containing merozoites). Cell rupture also occurs when the oocyst is released after the sexual reproduction stage. Destruction of enterocytes or lamina propria results in diarrhea, dehydration, weight loss, and severe hemorrhage. Antiprotozoal vaccines for animals include vaccines against coccidiosis for poultry, many of which are actually nonattenuated oocysts from various coccidian species. Anticoccidial treatment is often used at the time of vaccine administration. Interestingly, use of live coccidia vaccines in poultry houses can restore a drug-sensitive population of parasites to populations in which drug-resistant coccidia become prevalent. Live coccidiosis vaccines that incorporate attenuated oocysts and a nonliving subunit vaccine are also available. Anticoccidial compounds generally fall into one of two categories. The first are polyether ionophores which disrupt the proper intra and extracellular concentrations of the various cations and leads to cellular dysfunction. The second group includes compounds that cause an enzymatic reaction. The various classes of anticoccidial compounds and their mechanism of action are listed below. Polyether Ionophores fall into one of five categories including monovalent, monovalent glycosides, divalent, divalent glycosides, and divalent pyrole ethers. Their mode of actions is to form lipophilic complexes with alkali metal cations and to transport these ions across biological membranes. The end result is that the cell is unable to maintain the proper intra and extracellular concentrations of the various cations and leads to cellular dysfunction. A main way this occurs is by the Ionophores interfering with the K+/Na+ pump osmolarity. Ionophore drugs also allow some cycling of the coccidia in the bird which aids in producing immunity. Ionophores generally have lower rate of resistance development compared to the enzyme reaction drugs listed above and often allow some low level cycling of the coccidia in the host leading to host immunity. Anticoccidial drugs belonging to the polyether Ionophores include lasalocid, salinomycin, maduramicin, monensin, narasin, lonomycin, and semduramicin. Maxiban is toxic in turkeys and should not be used in this species, but is a safe drug for quail, pheasants and chickens Enzyme or metabolic blocking anticoccidial compounds include sulfonamides are folate antagonists and their mechanism of action (MOA) occurs by competitive inhibitors of PABA in the dihydropteroate synethetase reaction to make folate. Normally, folate is reduced to tetrahydrofolate, using NADPH as a co-factor, and is used to create and methylate DNA. 2,4-diaminopyrimidines act in a similar fashion and block the reduction of folate to tetrahydrofolate. The combination of sulfonamides and 2,4-diaminopyrimidines is synergistic and is active on first and second generation schizonts and perhaps sexual stages as well. Amprolium is a thiamine antagonist and acts by competitively inhibiting the active transport of thiamine. Care must be taken not overdose animals on amprolium or secondary complications including polioencephalomalacia may develop due to lack of thiamine. Coccidia are generally immunogenic and a single infection in an immunocompenent host will induce immunity to reinfection to some degree. However, exceptions to this generality have been noted. Immunity in coccidia occurs primarily as a result of the asexual replication, with the sexual stages contributing little additional protection. Immunity to a challenge inoculum is manifested as a reduction in clinical signs and reduced multiplication of the parasite. Circulating antibodies are effective at opsonization and cytopathological and enhancing the uptake of parasites of macrophages. The role of cell-mediated immunity has been shown to be the most important factor in host protection. Adoptive transfer of lymphocytes from Eimeria immunized animals to naïve animals leads 619

to protection when challenged. It is assumed that the importance of cell mediated immunity is the same in all vertebrate hosts of coccidia.

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Ticks and Diseases They Cause in Pets- Ehrlichiosis, Anaplasmosis, Cytauxzoonosis, and More Richard Gerhold, DVM, MS, PhD University of Tennessee Knoxville, TN

Tick-borne diseases are extremely important and emerging diseases in the United States. The area in which you live will influence the diseases that are circulating in the environment. Although diseases such as Lyme disease has received a great deal of attention, other important diseases including ehrlichiosis, Rocky Mountain spotted fever, anaplasmosis and cytauxzoonosis have been emerging in various areas. A good travel history is imperative given various species of ticks and tick-borne diseases are more common in certain geographical areas. More information on tick-borne disease distribution can be found at http://www.capcvet.org/parasite-prevalence- maps/

Diagnosis of tick-borne diseases: Serology vs PCR Testing is warranted on animals with the aforementioned clinical signs. PCR testing (detection of pathogen DNA) is more sensitive than serology for detection of Rocky Mountain spotted fever and Anaplasma/Ehrlichia species during the acute phase of the disease, prior to the development of an antibody response. Therefore, if an animal presents with acute signs suggestive of tick-borne disease (i.e. fever, lethargy, thrombocytopenia, leukopenia, arthropathy, neurologic dysfunction), the best test for diagnosis is the PCR. Whole blood (EDTA) should be obtained for the test, prior to antibiotic administration. Serology is useful for detection of chronic/persistent infections, during which the numbers of pathogens are lower or absent from circulation and cannot be detected as easily by PCR. This is particularly true for Lyme disease. This organism localizes in the tissues and is difficult to detect in the blood. It is important to note that antibodies to these tick-borne agents may persist for several months to years (especially for E. canis), so detection of antibodies does not distinguish current infection from previous exposure. Also, high seroprevalence to these agents has been documented in healthy dogs in endemic areas, such as the Southern USA, and most dogs exposed to Anaplasma or Ehrlichia species will not develop overt clinical disease. Therefore, PCR of skin or other tissues (not blood) and/or complete blood count is useful to determine if seropositive animals are currently infected and have clinical disease.

Identification of ticks Tick bodies are divided into two primary sections including fused head and thorax and abdomen. All adult and nymphal forms have 4 pairs legs and no antennae and all larval forms have 3 pairs of legs. The importance of determining larvae vs other stages include to determine the likelihood of tick being infected with various pathogens. Unless transovarial transmission occurs, larvae are unlikely to be infected with pathogens, while nymphs and adults have higher likelihood include with pathogens in transstadial transmission. Whereas hard ticks have scutum, soft ticks do not have scutum. Ticks are great vectors due to their ability to be persistent blood- suckers which attach firmly & feed slowly, long life spans, may be geographically widespread, resistant to environmental conditions, high reproductive potential, and can pass infective agents through egg to next generation and/or through successive stages. Ticks bites in themselves can lead to wounds and Inflammation from salivary proteins. Secondary infection and disease can be due to toxicosis, local necrosis, and tick paralysis. Tick bites predispose animals to secondary attacks by myiasis-producing flies. Soft tick have no scutum are soft, tough, leathery body, do not stay attached—instead take multiple small volumes of blood, and often feed at night. Soft ticks include Otobius megnini (Spinose Ear Tick) transmits relapsing fever caused by a Borrelia spp. (different than Borrelia burgdorferi which causes Lyme Disease). Spinose ear ticks are more common in western states that are west of 100th meridian Hard Ticks is largest family of ticks has a scutum (dorsal, hardened plate) that covers entire dorsum of males and forms an anterior shield in females. Hard ticks remain attached until engorged and then fall off to molt or lay eggs. General life cycle include:  Egg  6-legged larva  8-legged nymph  8-legged adult  Oviposition (egg laying) occurs off of the host  Nymphs and adults can be identified based on visual exam but often unable to distinguish larvae without microscopic exam Nymphs and adults are more likely to harbor pathogens than larvae—this is why you need to be able to distinguish larvae (6 legs) from nymphs/adults (8 legs).

Tick species All dermacentor spp.  Ornate ticks with eyes  Basis capitulum (mouth part) is rectangular if viewed from above and has stubby palps  Resembles Rhipicephalus (both have11 festoons, small rectangular patterns on posterior abdomen) 621

Dermacentor variabilis (American dog tick)  Eastern half of U.S. and west coast, but rare in Central US  Dogs, cats, humans, horses, cattle, fox, rodents, and other mammals  Can cause tick paralysis in humans, dogs, etc.  May take as little as 3 months, with favorable conditions, or up to 2 years  Principal vector of Rickettsia rickettsia - Rocky Mountain Spotted Fever (RMSF) and others in Spotted Fever Group  Infrequent vectors of tularemia, anaplasmosis, Babesia canis, Cytauxzoon felis Rhipicephalus sanguineus (brown dog tick)  Wide distribution  Rhipicephalus ticks are similar in appearance to Dermacentor, except they have a hexagonal basis capitulum. All stages parasitize on dogs and will attach to other animals, but usually not humans  Can survive indoors for months to possibly years without a blood meal  Domestic & kennel problem due to tropical nature of tick and because it cannot survival outdoors in North America  Vectors Babesia canis voglei, tularemia, Ehrlichia canis, RMSF Rhipicephalus (boophilus) annulatus (cattle fever tick)  Southern U.S. & Mexico—spreading North into lower Texas  Parasitize mainly on cattle; also deer, horses, donkeys, sheep, etc. in other countries, not U.S. and Mexico  1-host tick in U.S. and Mexico—re-emerging cases on US/Mexican border—large concern for USDA  First demonstrated tick-borne disease  Babesia bigemina (Texas cattle fever) VERY important disease to cattle industry—causes severe anemia and death in cattle and is a reportable tick species! All amblyomma spp.  Ornate ticks  Long mouth parts & commonly 11 festoons—allows one to differentiate from Ixodes spp which lack festoons Amblyomma americanum (Lone Star Tick)  Wide distribution, but mainly in southern U.S.  Large silver spot at apex of scutum on females – hence name “lone star”  All stages feed on wild & domestic animals, birds, & humans and is significant pest for humans & animals  Can transmit Coxiella burnetii (Q-fever), tularemia, Ehrlichia chaffeensis, Ehrlichia ewingii, RMSF, Cytauxzoon felis (cats)  Vectors agent of Southern Tick Associated Rash Infection (STARI) in humans  Cause of STARI is currently unknown—may actually be the host reaction to tick saliva—leads to swelling and pain at bite region Amblyomma maculatum (Gulf Coast Tick)  Southeastern US in Gulf coast region, but has expanded range recently  Ornate scutum – often confused with Dermacentor—examine mouth parts to differentiae  Adults attack nearly all animals & humans and can transmit Hepatozoon americanum Hepatozoonosis—dog must eat tick to be infected with Hepatozoon All Ixodes spp.  Inornate ticks and No festoons, has distinct anal groove anterolateral to anal orifice  Used for identification in NON-ENGORGED tick but can’t see groove in engorged ticks—use mouth parts instead Ixodes scapularis (Black-Legged Tick)  Wide distribution, in East, South, and Midwest U.S. Highest populations in upper Midwest and New England/midatlantic states  Primary Lyme disease (Borrelia burgdorferi) vector in Eastern US and Midwest  Vectors Babesia microti, Anaplasma phagocytophila Ixodes pacificus (California Black-Legged Tick) Primary Lyme disease vector in the West Coast

Tick-borne diseases Tick paralysis  Potentially fatal reaction to a paralyzing neuromuscular toxin secreted in the saliva of a female tick late in her feeding. Cattle, sheep, horses, dogs, and humans seem to be most affected.  Clinical signs include: headache, vomiting, general malaise, loss of motor function and reflexes, followed by paralysis that starts in the lower body and spreads to the rest of the body

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 Respiratory failure and death can result. Signs disappear rapidly when tick is removed, suggesting that the toxin is rapidly excreted or destroyed Lyme borreliosis  Agent: Borrelia burgdorferi  Vector: Ixodes scapularis (Eastern and Midwestern US), Ixodes pacificus (Western US)  Geographical distribution: New England and mid-Atlantic states, upper Mid-west, and Pacific coast.  Animal health: Major cause of canine and equine disease, including endocarditis and joint pain. Most cases occur in the spring and summer, during nymphal emergence, and in late fall and winter, during adult emergence.  Human health: Acute and chronic diseases including joint pain, heart disease, and neurological disorders. Most cases occur in the spring and summer, during nymphal emergence, and in late fall and winter, during adult emergence.  Diagnoses: Lyme disease is diagnosed using serology tests, bacterial cultures, and/or PCR of tissue (NOT BLOOD). Blood may be used for PCR in very acute cases, otherwise tissue biopsy is needed. Predictive value influences serological test interpretations—only treat animals with clinical signs suggestive of disease!!! Rocky Mountain Spotted Fever  Agent: Rickettsia rickettsia  Sometimes placed in “Spotted Fever” disease group  Vector: Dermacentor variabilis Geographical distribution: Eastern US mainly. Most frequently reported tick borne disease in the eastern US. Animal health: Recent evidence has shown that untreated RMSF may lead to death of the affected animal. Clinical signs include whole body pain and are painful on palpation. Cytauxzoon felis Piroplasm of cats. Bobcats are reservoir host that is transmitted by Amblyomma americanum. Clinical signs: fever, dehydration, icterus, lymphadenomegaly, and hepatosplenomegaly. Treatment with atovaquone plus azithromycin. Diagnosis: PCR, blood smear (negative blood smear does not rule out infection) since early stage only see schizonts in macrophages. Prevention: Keep cats indoors!! Use preventative for tick infestation Anaplasma phagocytophilum  Intracellular rickettsia that causes human granulocytic anaplasmosis  Infects granulocytes and leads to bleeding, fever, leukopenia,  Clinical signs/symptoms may be worse with co-infection with Lyme or Babesia  Vectored by Ixodes scapularis so same geographical distribution as Lyme Disease. Can be transmitted by blood transfusion.  Diagnosis: clinical signs, PCR (acute cases), serology (chronic), CBC to look for leukopenia, Blood smear to look for morulae in granulocytes.  Don’t treat animals that are clinically normal but are only seropositive—potential false positive due to positive predictive value.  Treatment with doxycycline or minocycline Anaplasma platys  Intracellular rickettsia that causes infectious cyclic thrombocytopenia in dogs  Common clinical signs include bleeding, due to cyclic thrombocytopenia…may be worse with co-infection with Ehrlichia canis, which is transmitted by same tick.  Transmitted by Rhipicephalus sanguineus –worldwide distribution  Diagnosis: clinical signs, PCR (acute cases), serology (chronic). Don’t treat animals that are clinically normal but are only seropositive—potential false positive due to positive predictive value.  Treatment with doxycycline or minocycline Ehrlichia canis  Intracellular rickettsia that causes canine ehrlichosis  Infects monocytes and leads to fever, anorexia, lethargy, thrombocytopenia, lymphadenopathy, edema, bone marrow suppression.  The acute stage is mainly due to a vasculitis. E. canis replicates in monocytes. The infected monocytes bind to vascular endothelial cells and leads to a vasculitis  Transmitted by Rhipicephalus sanguineus –worldwide distribution  Diagnosis: clinical signs, PCR (acute cases), serology (chronic), CBC to look for leukopenia, Blood smear to look for morulae in monocytes  Don’t treat animals that are clinically normal but are only seropositive—potential false positive due to positive predictive value. Treatment with doxycycline or minocycline 623

Ticks and the Diseases they Cause in Pets and People: Lyme Borreliosis, Tick Paralysis, Rocky Mountain Spotted Fever Richard Gerhold, DVM, MS, PhD University of Tennessee Knoxville, TN

Tick-borne diseases are extremely important and emerging diseases in the United States. The area in which you live will influence the diseases that are circulating in the environment. Although diseases such as Lyme disease has received a great deal of attention, other important diseases including ehrlichiosis, Rocky Mountain spotted fever, anaplasmosis and cytauxzoonosis have been emerging in various areas. A good travel history is imperative given various species of ticks and tick-borne diseases are more common in certain geographical areas. More information on tick-borne disease distribution can be found at http://www.capcvet.org/parasite- prevalence-maps/

Diagnosis of tick-borne diseases: Serology vs PCR Testing is warranted on animals with the aforementioned clinical signs. PCR testing (detection of pathogen DNA) is more sensitive than serology for detection of Rocky Mountain spotted fever and Anaplasma/Ehrlichia species during the acute phase of the disease, prior to the development of an antibody response. Therefore, if an animal presents with acute signs suggestive of tick-borne disease (i.e. fever, lethargy, thrombocytopenia, leukopenia, arthropathy, neurologic dysfunction), the best test for diagnosis is the PCR. Whole blood (EDTA) should be obtained for the test, prior to antibiotic administration. Serology is useful for detection of chronic/persistent infections, during which the numbers of pathogens are lower or absent from circulation and cannot be detected as easily by PCR. This is particularly true for Lyme disease. This organism localizes in the tissues and is difficult to detect in the blood. It is important to note that antibodies to these tick-borne agents may persist for several months to years (especially for E. canis), so detection of antibodies does not distinguish current infection from previous exposure. Also, high seroprevalence to these agents has been documented in healthy dogs in endemic areas, such as the Southern USA, and most dogs exposed to Anaplasma or Ehrlichia species will not develop overt clinical disease. Therefore, PCR of skin or other tissues (not blood) and/or complete blood count is useful to determine if seropositive animals are currently infected and have clinical disease.

Identification of ticks Tick bodies are divided into two primary sections including fused head and thorax and abdomen. All adult and nymphal forms have 4 pairs legs and no antennae and all larval forms have 3 pairs of legs. The importance of determining larvae vs other stages include to determine the likelihood of tick being infected with various pathogens. Unless transovarial transmission occurs, larvae are unlikely to be infected with pathogens, while nymphs and adults have higher likelihood include with pathogens in transstadial transmission. Whereas hard ticks have scutum, soft ticks do not have scutum. Ticks are great vectors due to their ability to be persistent blood- suckers which attach firmly & feed slowly, long life spans, may be geographically widespread, resistant to environmental conditions, high reproductive potential, and can pass infective agents through egg to next generation and/or through successive stages. Ticks bites in themselves can lead to wounds and Inflammation from salivary proteins. Secondary infection and disease can be due to toxicosis, local necrosis, and tick paralysis. Tick bites predispose animals to secondary attacks by myiasis-producing flies. Soft tick have no scutum are soft, tough, leathery body, do not stay attached—instead take multiple small volumes of blood, and often feed at night. Soft ticks include Otobius megnini (Spinose Ear Tick) transmits relapsing fever caused by a Borrelia spp. (different than Borrelia burgdorferi which causes Lyme Disease). Spinose ear ticks are more common in western states that are west of 100th meridian Hard Ticks is largest family of ticks has a scutum (dorsal, hardened plate) that covers entire dorsum of males and forms an anterior shield in females. Hard ticks remain attached until engorged and then fall off to molt or lay eggs. General life cycle include:  Egg  6-legged larva  8-legged nymph  8-legged adult  Oviposition (egg laying) occurs off of the host  Nymphs and adults can be identified based on visual exam but often unable to distinguish larvae without microscopic exam Nymphs and adults are more likely to harbor pathogens than larvae—this is why you need to be able to distinguish larvae (6 legs) from nymphs/adults (8 legs).

Tick species All dermacentor spp.  Ornate ticks with eyes  Basis capitulum (mouth part) is rectangular if viewed from above and has stubby palps  Resembles Rhipicephalus (both have11 festoons, small rectangular patterns on posterior abdomen) 624

Dermacentor variabilis (American dog tick)  Eastern half of U.S. and west coast, but rare in Central US  Dogs, cats, humans, horses, cattle, fox, rodents, and other mammals  Can cause tick paralysis in humans, dogs, etc.  May take as little as 3 months, with favorable conditions, or up to 2 years  Principal vector of Rickettsia rickettsia - Rocky Mountain Spotted Fever (RMSF) and others in Spotted Fever Group  Infrequent vectors of tularemia, anaplasmosis, Babesia canis, Cytauxzoon felis Rhipicephalus sanguineus (brown dog tick)  Wide distribution  Rhipicephalus ticks are similar in appearance to Dermacentor, except they have a hexagonal basis capitulum. All stages parasitize on dogs and will attach to other animals, but usually not humans  Can survive indoors for months to possibly years without a blood meal  Domestic & kennel problem due to tropical nature of tick and because it cannot survival outdoors in North America  Vectors Babesia canis voglei, tularemia, Ehrlichia canis, RMSF Rhipicephalus (boophilus) annulatus (Cattle Fever Tick)  Southern U.S. & Mexico—spreading North into lower Texas  Parasitize mainly on cattle; also deer, horses, donkeys, sheep, etc. in other countries, not U.S. and Mexico  1-host tick in U.S. and Mexico—re-emerging cases on US/Mexican border—large concern for USDA  First demonstrated tick-borne disease  Babesia bigemina (Texas cattle fever) VERY important disease to cattle industry—causes severe anemia and death in cattle and is a reportable tick species! All Amblyomma spp.  Ornate ticks  Long mouth parts & commonly 11 festoons—allows one to differentiate from Ixodes spp which lack festoons Amblyomma americanum (Lone Star Tick)  Wide distribution, but mainly in southern U.S.  Large silver spot at apex of scutum on females – hence name “lone star”  All stages feed on wild & domestic animals, birds, & humans and is significant pest for humans & animals  Can transmit Coxiella burnetii (Q-fever), tularemia, Ehrlichia chaffeensis, Ehrlichia ewingii, RMSF, Cytauxzoon felis (cats)  Vectors agent of Southern Tick Associated Rash Infection (STARI) in humans  Cause of STARI is currently unknown—may actually be the host reaction to tick saliva—leads to swelling and pain at bite region Amblyomma maculatum (Gulf Coast Tick)  Southeastern US in Gulf coast region, but has expanded range recently  Ornate scutum – often confused with Dermacentor—examine mouth parts to differentiae  Adults attack nearly all animals & humans and can transmit Hepatozoon americanum Hepatozoonosis—dog must eat tick to be infected with Hepatozoon All Ixodes spp.  Inornate ticks and No festoons, has distinct anal groove anterolateral to anal orifice  Used for identification in NON-ENGORGED tick but can’t see groove in engorged ticks—use mouth parts instead Ixodes scapularis (Black-Legged Tick)  Wide distribution, in East, South, and Midwest U.S. Highest populations in upper Midwest and New England/midatlantic states  Primary Lyme disease (Borrelia burgdorferi) vector in Eastern US and Midwest  Vectors Babesia microti, Anaplasma phagocytophila Ixodes pacificus (California Black-Legged Tick) Primary Lyme disease vector in the West Coast

Tick-borne diseases Tick paralysis Potentially fatal reaction to a paralyzing neuromuscular toxin secreted in the saliva of a female tick late in her feeding. Cattle, sheep, horses, dogs, and humans seem to be most affected. Clinical signs include: headache, vomiting, general malaise, loss of motor function and reflexes, followed by paralysis that starts in the lower body and spreads to the rest of the body

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Respiratory failure and death can result. Signs disappear rapidly when tick is removed, suggesting that the toxin is rapidly excreted or destroyed Lyme Borreliosis  Agent: Borrelia burgdorferi  Vector: Ixodes scapularis (Eastern and Midwestern US), Ixodes pacificus (Western US)  Geographical distribution: New England and mid-Atlantic states, upper Mid-west, and Pacific coast.  Animal health: Major cause of canine and equine disease, including endocarditis and joint pain. Most cases occur in the spring and summer, during nymphal emergence, and in late fall and winter, during adult emergence.  Human health: Acute and chronic diseases including joint pain, heart disease, and neurological disorders. Most cases occur in the spring and summer, during nymphal emergence, and in late fall and winter, during adult emergence.  Diagnoses: Lyme disease is diagnosed using serology tests, bacterial cultures, and/or PCR of tissue (NOT BLOOD). Blood may be used for PCR in very acute cases, otherwise tissue biopsy is needed. Predictive value influences serological test interpretations—only treat animals with clinical signs suggestive of disease!!! Rocky Mountain Spotted Fever  Agent: Rickettsia rickettsia  Sometimes placed in “Spotted Fever” disease group  Vector: Dermacentor variabilis  Geographical distribution: Eastern US mainly. Most frequently reported tick borne disease in the eastern US. Animal health: Recent evidence has shown that untreated RMSF may lead to death of the affected animal. Clinical signs include whole body pain and are painful on palpation. Anaplasma phagocytophilum  Intracellular rickettsia that causes human granulocytic anaplasmosis  Infects granulocytes and leads to bleeding, fever, leukopenia,  Clinical signs/symptoms may be worse with co-infection with Lyme or Babesia  Vectored by Ixodes scapularis so same geographical distribution as Lyme Disease. Can be transmitted by blood transfusion.  Diagnosis: clinical signs, PCR (acute cases), serology (chronic), CBC to look for leukopenia, Blood smear to look for morulae in granulocytes.  Don’t treat animals that are clinically normal but are only seropositive—potential false positive due to positive predictive value.  Treatment with doxycycline or minocycline

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Non Tick-Borne Diseases: Avian and Swice Influenza, Bartonellosis, Leptospirosis, Rabies, and More Richard Gerhold, DVM, MS, PhD University of Tennessee Knoxville, TN

Anthrax  Bacillus anthracis  Ruminant reservoir  Human:  Reportable disease Animals  Sudden death  Bloody discharge from orifices that DOES NOT CLOT  Do not necropsy; burn carcass, send ear only to lab for confirmation of disease Human  95% cutaneous  Small, painless, red pruritic papules on skin that ulcerate; Tx w/ AB’s  Inhalation  FATAL URI with fever, shock and respiratory distress; death in 24h

Avian chlamydiosis  “Ornithosis/Psittacosis”  Chlamydophila psittaci  Bird reservoir  Humans have flu like symptoms o Fever, chills, headache, muscle aches, URI & LRI symptoms  Reportable disease  Birds are often subclinical o Yellow-green diarrhea, conjunctivitis, nasal discharge, respiratory difficulty o Bacteria can persist in dander/heating/air ducts  Responds to antibiotics Avian and swine influenza  Normally not infective to humans  Mutations/variations can occur that can lead to efficient transmission and binding to human cell receptors  Wear PPE when dealing with avian and swine that are suffering from respiratory disease Brucellosis  Brucella abortus, B. melitensis, B. suis, B. canis  Ruminants, horses, swine, dogs  Human  Reportable disease Animal-to-animal or –to-human transmission  Ingestion of materials contaminated with infected birth fluids.  Coitus (pigs & dogs)  HUMAN: Farmers moving placentas, etc. OR… Inoculation with the Strain 19 vaccine…OR…Consumption of infected milk, or cleaning or eating infected feral swine Animals  Abortion  Orchitis,  Infertility

Cat scratch fever  Bartonella henselae  Cats o Cats have bacteria, asymptomatic

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o Fleas ingest, shed in flea feces  Human o Flea feces contaminate human wound o Lymphadenopathy  Self-limiting disease (2-3wks) or chronic malaise that can mimic Lyme disease  Humans: Infection worse in immunocompromised people o Local skin rxn & enlarged l.n. in area of bite o 1/3 of people will have fever, headache & malaise  PREVENTION = Flea control!  Problem in nursing homes if animals are not well cared for

Gastointestinal disease  Campylobacter jejuni & C. coli o Birds & mammals (Chickens, cattle, pets)  Cryptosporidium sp. o Mammals, esp. cattle  Enteric Bacteria o Salmonella, E. coli  Wash hands! Keep things out of mouth!  Most self- limiting diarrhea in humans if immunocompetent  Food ingestion is common means of infection; direct contact possible

Leptospirosis  Leptospirosis is a zoonotic disease with a worldwide distribution and can potentially infect all mammals.  Leptospirosis is an aerobic, gram negative spirochete bacterial infection caused by members of the genus Leptospira, which contain around 220 distinct pathogenic serovars. o Common maintenance hosts of certain pathogenic Leptospiral serovars: . Dogs – Canicola . Pigs, cattle, oppossums, and skunks – Pomona . Raccoons and muskrats – Grippotyphosa . Cattle – Hardjo . Rats – Icterohaemorrhagiae . Pigs and possibly mice and horses – Bratislava  Leptospirosis is typically transmitted by direct contact with the urine or other body fluids of infected animals or indirectly through contact with water or soil that has been contaminated with infected urine/body fluids.  An array of clinical effects have been reported, ranging from mild, subclinical infection to multiple organ failure and death.  Clinical signs of leptospirosis in wildlife have not been thoroughly documented, but it is believed that most infected wildlife are asymptomatic and serve as maintenance hosts for transmission of the organism to domestic animals and humans.  Clinical signs of leptospirosis in domestic animals and humans is species dependent but generally includes alterations in liver and kidney function. Infections in these incidental hosts can be asymptomatic or may result in kidney and/or liver failure, fever, jaundice, and death Plague  Yersinia pestis  Two forms Bubonic and pneumonic  Bubonic o Rodents, lagomorphs o Spread through flea bites  Pneumonic o Cats, man o Spread through aerosol

 Dogs are resistant but can carry the fleas  Reportable disease in US 628

 Tx systemic abs Clinical signs in cats Clinical signs vary depending on what form of plague is present. Plague should be suspected in any cat exhibiting a fever in an endemic region. Cats with bubonic plague typically have fever, dehydration, lethargy, weight loss, hyperesthesia, and lymphadenopathy. The submandibular, cervical, and retropharyngeal lymph nodes are usually involved if the cat acquires infection by ingestion of infected prey. Lymph nodes will enlarge, form abscesses, and may spontaneously drain.

Toxoplasmosis Domestic and wild felids are the definitive host for the protozoan Toxoplasma gondii. The oocysts of Toxoplasma are extremely environmentally resistant and human and animal infections can occur months or possibly even years after the cat has excreted the oocysts. As such, cat feces-contaminated gardens, sandboxes, and other outdoor recreational areas may serve as a source of infection for humans and animals. In toxoplasmosis, infection occurs primarily by ingestion of sporulated oocyst in cat feces- contaminated soil or water or tissue cysts in undercooked or raw meat. Upon ingestion of tissue or environmental cysts, the parasites are released, penetrate the intestinal bilayer, and replicate rapidly inside host cells. Currently, toxoplasmosis is considered the third most frequently diagnosed food borne disease in the US and approximately 60 million US citizens are infected with the parasite. Higher frequency of T. gondii seroprevalence has been disclosed in free-roaming cats compared to pet cats, with the lowest seroprevalence in cats kept indoors. Although the risk of infection of human infection through ingestion of oocysts has been less common than infection from ingestion of undercooked or raw meat, recent research suggests otherwise. A recently developed sporozoite specific antibody has been developed which allows for serological distinction between oocyst and tissue cyst infection given that sporozoites are only present in oocysts. Of 163 individuals in acute stage of toxoplasmosis infection 103 (63%) were positive for sporozoite-specific antibody indicating that the majority of human infection was due to oocyst infection from cat-feces contaminated environments. Clinically, Toxoplasma infections appear as abortions, and birth defects, as ocular diseases, neurological impairment leading to blindness, particularly hydrocephalus, in humans. Furthermore, toxoplasmosis is also a significant risk in individuals undergoing immuosuppressive therapy including transplant recipients. Toxoplasmosis is also a major cause of systemic infection and death for immunosuppressed (e.g., HIV/AIDS) patients. An increased of risk of neuro-inflammatory diseases including schizophrenia, autism, Alzheimers, and other has been suggested with T. gondii; more research is warranted to elucidate the neurological impacts of T. gondii.

Tick-borne diseases Tick paralysis Potentially fatal reaction to a paralyzing neuromuscular toxin secreted in the saliva of a female tick late in her feeding. Cattle, sheep, horses, dogs, and humans seem to be most effected. Clinical signs include: headache, vomiting, general malaise, loss of motor function and reflexes, followed by paralysis that starts in the lower body and spreads to the rest of the body Respiratory failure and death can result. Signs disappear rapidly when tick is removed, suggesting that the toxin is rapidly excreted or destroyed

Lyme borreliosis  Agent: Borrelia burgdorferi  Vector: Ixodes scapularis (Eastern and Midwestern US), Ixodes pacificus (Western US)  Geographical distribution: New England and mid-Atlantic states, upper Mid-west, and Pacific coast.  Animal health: Major cause of canine and equine disease, including endocarditis and joint pain. Most cases occur in the spring and summer, during nymphal emergence, and in late fall and winter, during adult emergence.  Human health: Acute and chronic diseases including joint pain, heart disease, and neurological disorders. Most cases occur in the spring and summer, during nymphal emergence, and in late fall and winter, during adult emergence.  Diagnoses: Lyme disease is diagnosed using serology tests, bacterial cultures, and/or PCR of tissue (NOT BLOOD). Blood may be used for PCR in very acute cases, otherwise tissue biopsy is needed. Predictive value influences serological test interpretations—only treat animals with clinical signs suggestive of disease!!!

Rocky Mountain Spotted Fever  Agent: Rickettsia rickettsia  Sometimes placed in “Spotted Fever” disease group  Vector: Dermacentor variabilis

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 Geographical distribution: Eastern US mainly. Most frequently reported tick borne disease in the eastern US. Animal health: Recent evidence has shown that untreated RMSF may lead to death of the affected animal. Clinical signs include whole body pain and are painful on palpation. May see petechial and ecchymotic hemorrhages

Rabies Although rabies is detected most frequently in various wildlife populations in the U.S., multiple recent studies have disclosed that human exposure to rabies is primarily associated with domestic cats due to people being more likely to come in contact with cats. Rabies virus is transmitted via saliva from one host to another primarily via a bite from a rabid animal. Following a bite of a rabid animal and virus inoculation, the virus replicates in neurons and disseminates via the nervous system. Later in the infection the virus can be found in highly innervated organs including cornea, skin, and salivary glands Rabies leads to various neurological impairment symptoms and the disease is invariably fatal. 92% of actual human rabies infection has been associated with bat-associated rabies virus mainly due to bat bites not being noticed by humans. Only 1% of healthy bats and 11% of sick bats are found to be rabid. Effort should be made to make houses and areas unattractive to raccoons, skunks, and other rabies hosts.

Visceral larval migrans Baylisascaris procyonis is a roundworm of raccoons and birds are infected by ingesting larvated eggs in the environment. Dogs, kinkajous, ringtailed coatis can also serve as the definite host for B. procyonis and can shed eggs. The distribution of B. procyonis has been increasing recently. Larval migrans of B. procyonis can result in numerous neurological impairment clinical signs including encephalitis, circling, seizures, and death. Necropsy diagnostics include histopath examination and PCR. Limiting raccoon access to yard and making the areas unattractive to raccoons is the main way to prevent this disease.

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Introduction to Laparoscopy: Achieving Big Things Through Small Holes Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

Laparoscopic and thoracoscopic techniques provide minimally invasive access to the abdominal and thoracic cavities, respectively. They allow both diagnostic evaluation of various organs and tissues as well as allowing an ever growing armamentarium of therapeutic interventions to be carried out through small port incisions. Performing successful minimally invasive surgery relies heavily on patient selection and adequate training, but equally important is having good quality equipment. Attempting these procedures without the correct equipment might not only compromise the safety of the patient but can be very frustrating for the surgeon. Prior to performing a minimally invasive procedure it is important that owners are informed of the possible need to convert to an open approach if the need arises. It is therefore vital to have regular instrumentation for open surgery available on the operating room table should conversion to open surgery be necessary.

Instrumentation Imaging - rigid telescopes The telescope allows transmission of the visual image from the surgical site to the camera. Quality of telescopes has risen rapidly in recent years especially with the introduction of the rod lens system. These telescopes employ a series of glass lenses arranged in a narrow tube to transmit light. The important variables to consider when choosing a telescope are the diameter, the length and the angulation at the tip. Probably the most versatile telescope for laparoscopy and thoracoscopy in small animals is the 5 mm diameter telescope. This is adequate for most dogs and cats. A smaller 3 mm diameter 14 cm long telescope (Karl Storz Veterinary Endoscopy) or a traditional 2.7 mm arthroscope can be used for smaller dogs and cats. Angulation of the tip of the telescope dictates the direction of the field of view. The 0º telescope will provide an image of what lies directly in front of the tip of the scope which is adequate for most abdominal procedures. The 30º telescope provides a view that is offset by 30º. Although somewhat more difficult to manipulate initially, they are helpful as by rotation of the light post (and therefore the telescope), a greater field of view is obtained. Imaging – cameras The image that is transmitted through the lenses of the telescope is captured by the camera and turned into a video image. The camera attaches to the head of the telescope and has a cord that feeds into the camera control box housed on the tower. The quality of the endoscopic video camera depends on the camera control unit or “chip”. One-chip cameras use a single computer chip to process the colors the camera sees whereas in a 3-chip camera each chip processes a separate primary color, namely red, green or blue. One-chip cameras are satisfactory for most applications but three-chip cameras have superior optical clarity and color reproduction and provide images that are of photographic or broadcast quality. Alterations of the focus and field of vision size are usually controlled by rings located on the camera head with more modern cameras allowing the operator control of multiple functions such as white balance, other menu alterations, and image and video recording via buttons also located on the camera head.

Imaging - tower components The light source Modern light sources are usually powered by either halogen or xenon. Xenon is preferable as it emits a high intensity light that reproduces the color of natural light closely. Light sources between 150-300 watts are recommended to ensure good picture quality. Care of the fiberoptic light cable is also essential for optimal performance as if the fibers break or the tips are not regularly cleaned image quality will suffer. Care should always be taken to know where the tip of the telescope or light cable (when not attached to the telescope) is while the light source is fully powered. When resting on the table adjacent to drapes or in body cavities, or when resting against tissues, thermal burns can occur rapidly. When not directly in use, the power to the light source should always be turned down. The insufflator

During laparoscopy a mechanical insufflator regulates the flow of gas (usually CO2) into the abdomen during creation of a pneumoperitoneum. Pneumoperitoneum allows the working space necessary to manipulate instruments and organs during laparoscopic procedures. Modern insufflators allow monitoring of the pressure within the abdominal cavity and prevent pressure rises above preset levels. In dogs, intra-abdominal pressure of 15 mm Hg is considered to result in physiologically acceptable levels of cardiorespiratory depression while providing more than adequate working space in most patients.1 Intra-abdominal pressures of 8-10 mm Hg generally provide adequate working space in most dogs and cats. The Monitor Usually located at the top of the “tower”, a high quality medical grade cathode ray tube or flat panel monitor is essential to be able to view structures clearly and should be large enough so that the surgeon can see images from across the surgical table. It is very

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important to consider optimal tower location for any given procedure during preoperative planning. This will minimize the need for cumbersome intra-operative relocation of the tower while maximizing the ability to maintain the straight line viewing axis from the surgeon to the lesion being operated and on to the monitor. Data recording devices Providing a record of images or video of the procedure is very helpful for patient medical records as well as client and veterinarian education and publication purposes. The simplest device for image capture is the video printer that will print single images in surgery. Video recorders can be used to record whole procedures that can then later be edited. Digital capture devices are now commonplace which provide perhaps the most versatile storage and distribution medium. Still images and videos can be captured, stored on the units’ hard drive or be easily downloaded to CD, DVD or connected via USB ports to external storage devices such as flash drives or portable hard drives (e.g. AIDA -vet device, Karl Storz Veterinary Endoscopy). Trocars and cannulas Establishing access ports using cannulas is essential for laparoscopic procedures to allow atraumatic repeated instrument exchanges. For laparoscopy where insufflation is used, maintenance of an airtight seal to prevent leakage of insufflation gas during laparoscopy is also accomplished using cannulae. A large variety of sizes and designs of trocars and cannulae are available. Choices to be considered include the use of single-use disposable versus resterilized non-disposable cannulae, blunt versus sharp trocars and trocar-cannula assemblies versus trocar-less cannulae. Single-use disposable cannulae are generally made of lightweight plastics and are less likely to slide out of port incisions; a common occurrence in small dogs and cats. Blunt trocars should always be used during establishment of the first (camera) port to avoid iatrogenic damage to underlying organs prior to the establishment of a pneumoperitoneum or pneumothorax. Instrument ports can then safely be established using sharp-tipped trocars that can be placed under direct visualization from within the body cavity. Trocar-less threaded cannulae (Endotip, Karl Storz Endoscopy) are also popular for use in small animals. These blunt-tipped threaded cannulae are screwed into position and are well retained by the body wall due to the threads present on the cannula shaft. They also allow the laparoscope to be inserted into the cannulae during placement to visualize penetration of the body cavity during entry. Surgical instruments Almost all of the instruments used for open surgical procedures are available in laparoscopic versions including scissors, various grasping forceps and cup biopsy forceps. The 5 mm sized instruments are usually used for small animal procedures although 2, 3 and 10 mm are also available. A simple blunt probe is one of the most useful instruments for carefully moving organs in a non-traumatic fashion. Other components of a basic instrument set required for most laparoscopic and thoracoscopic interventions include a Metzenbaum and hook (suture-cutting) scissors, Kelley hemostats, Babcock forceps (5 and 10 mm versions), and cup biopsy forceps. For procedures requiring more intricate dissection various sizes of right-angle forceps (5 and 10 mm) are useful. A knot-pusher is an instrument required when extra-corporeal knot tying is used. Knots tied outside the body cavity are pushed into position through the cannula and around the vessel or other structure being ligated. Various forms of laparoscopic retractors are also available including fan retractors, and various forms of inflatable retractors that are necessary when performing certain procedures where visualization is obscured by certain other organs or by the movement of the organ being operated. Laparoscopic needle holders are necessary for intracorporeal suturing. These are generally used in pairs and are available with various styles of tip, one of the most popular of which is the parrot-jaw.

Anesthetic considerations The most important anesthetic considerations for laparoscopic surgery are related to abdominal insufflation. Respiratory and cardiovascular depression can occur secondary to excessive pressure exerted on the diaphragm and vascular structures of the peritoneal cavity. Intra-abdominal pressures should be maintained at ~10-12 mmHg and certainly below 15 mmHg to prevent potential cardiovascular and respiratory depression. Carbon dioxide (CO2) is the gas of choice to achieve a pneumoperitoneum. Insufflation with air may result in fatal air embolism and the use of nitrous oxide (N2O) is discouraged due to the potential for combustion when electrocautery devices are used. Hypercarbia can occur during pneumoperitoneum for two main reasons: increased pressure on the diaphragm causing a reduction in tidal volume, thus compromising ventilation, and rapid absorption of CO2 through the peritoneal lining. It is therefore recommended that monitoring of CO2 via either capnography or blood gas analysis be performed and ventilation adjusted accordingly.

Principles of abdominal access Veress needle technique A Veress needle is a specialized instrument used for creation of pneumoperitoneum or pneumothorax . It consists of a sharp-tipped needle component that houses within it a blunt-tipped obturator loaded on a spring-like mechanism. The sharp component of the needle will penetrate the body wall whose resistance will force the blunt obturator to retract into the shaft. Upon penetration of the

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body wall, however, resistance is lost, allowing the blunt-tipped obturator to spring forward thereby shielding the abdominal viscera from injury. Modified Hasson technique The modified Hasson technique avoids the blind introduction of a sharp needle and cannula into the peritoneal cavity. It is performed by making a 1 cm skin incision just caudal to the umbilicus which is followed by blunt dissection to the linea alba. A 3-4 mm incision is made through the linea alba and a trocar-cannula assembly is introduced into the peritoneal cavity. A blunt-tipped trocar should be used to prevent injury to the abdominal organs. Penetration into the peritoneal cavity can be confirmed by observation of falciform fat through the incision prior to inserting the trocar. The insufflator line is attached to the cannula and the abdomen is insufflated. Upon establishing a pneumoperitoneum, the abdominal cavity should become tympanic. Placement of instrument portals Once the camera portal has been established as many instrument portals as are necessary for a given procedure can be placed. Instrument portals are usually placed using direct visualization from inside the body cavity now that access for the telescope has been achieved. A stab incision with a scalpel blade is made over the proposed site of the portal and a trocar-cannula assembly or trocarless cannula is inserted through the deeper layers of the body wall. The surgeon can then observe from within the body cavity as the cannula enters thereby avoiding any iatrogenic damage to organs.

Achieving hemostasis A variety of methods for achieving hemostasis within body cavities during laparoscopic and thoracoscopic procedures are available. Hemostatic agents Topical hemostatic agents such as gelatin sponges (Gelfoam©) and oxidized regenerated cellulose (Surgicel©) can be passed down laparoscopic ports and applied as in open surgery but they can be tedious to manipulate into position. Newer fibrin “glue” sealants are also becoming available for laparoscopic applications in human medicine and may be used for veterinary applications in the future. Laparoscopic hemostatic clips A variety of disposable or non-disposable laparoscopic hemoclip appliers are available. Reusable sterilized clip appliers (M/L-10 reusable multi-fire hemoclip applier, Microline Pentax) are loaded with clip cartridges and are more cost effective than disposable devices. Multi-fire clip appliers that allow several clips to be applied without withdrawal of the device minimize instrument exchanges and surgical time. The use of laparoscopic hemoclips in veterinary patients has been evaluated in a laparoscopic ovariohysterectomy model and was shown to be safe and effective for ovarian pedicle ligation; however, hemoclip application was shown to be more time- consuming than the use of a vessel-sealing device for this application.2 Monopolar and bipolar electrosurgery Both monopolar and bipolar electrosurgery can be used in minimally invasive surgery. Monopolar electrosurgery should however be used with great caution in MIS as several potentially hazardous problems can occur. A defect in the insulation of the instrument shaft can result in the passage of current to tissues that are not in the visual field resulting in iatrogenic injury. Direct coupling injuries can occur when the instrument through which the electric current is passed comes into contact with the telescope, or other instrument, resulting in iatrogenic damage to tissues that may lie outside the visual field. Bipolar electrosurgery is safer as it is usually of lower voltage current and the electrical current is only passed between the tips of the bipolar instrument used. Vessel-sealing devices A more recent development in MIS is the increasing use of vessel-sealing devices. Vessel-sealing devices are very helpful for hemostasis and simultaneously sealing and cutting a variety of tissues. They work by a combination of pressure exerted on tissue when the tissue is crushed in the tips of the device, followed by the application of bipolar or ultrasonic energy applied to the tissue. This process allows the elastin and collagen in the vessel wall to be sealed together permanently. A variety of units are currently available. Two bipolar electrocautery devices are the Ligasure™ (Valleylab, Tyco Healthcare Group) and the Enseal™ (SurgRX Inc.). Both devices have tips that are indicated to seal arteries and veins up to 7 mm in diameter. The Ligasure has the advantage of sensing the tissue impedance within the jaws of the tip that then adjusts the energy output from the generator accordingly to ensure a safe and effective seal. A second-generation Ligasure device known as the Force Triad™ is now available that provides a much more rapid seal cycle. The Harmonic Scalpel® (Ethicon Endo-surgery) is a device that uses ultrasonic energy to cut and coagulate tissue. The Harmonic Ace® tip is indicated to seal vessels up to 5 mm in diameter. Several reports have compared these devices with respect to the degree of lateral thermal spread, bursting pressures and sealing time although the results of these studies are often conflicting.3,4 Overall, however, all produce supra-physiological bursting pressures of at least three times systolic blood pressure.3 For the Ligasure lateral thermal spread ranged from 1.5-3.2 mm in one study with a greater degree of thermal spread seen as vessel size increased.5 Although generally very safe, care must nevertheless be taken when these devices are used adjacent to neurovascular or other vital structures. They are also not indicated for sealing of non-vascular luminal organs such as bile duct or lung tissue. Other vessel-sealing technologies are emerging onto the market constantly.

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References 1. Duke T, Steinacher SL, Remedios RM. Cardiopulmonary effects of using carbon dioxide for laparoscopic surgery in dogs. Vet Surg 1996;25:77-82 2. Mayhew, P.D. and Brown, D.C. Comparison of three techniques for ovarian pedicle hemostasis during laparoscopic-assisted ovariohysterectomy. Vet Surg 2007; 36:541-547. 3. Person B, Vivas DA, Ruiz D et al. Comparison of four energy-based vascular sealing and cutting instruments: a porcine model. Surg Endosc 2008;22:534-538 4. Lambertson GR, Hsi RS, Jin DH et al. Prospective comparison for four laparoscopic vessel ligation devices. J Endourol 2008;22:2307-2312 5. Carbonell AM, Joels CS, Krecher KW et al. A comparison of laparoscopic bipolar vessel sealing devices in the hemostasis of small, medium and large-sized arteries. J Laparoendosc Adv Surg Tech 2003;13:377-380

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Ear Surgery: Pick the Right Technique and Avoid Complications Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

Surgery of the ear is commonly indicated in small animal practice for a variety of causes including otitis externa, otitis media as well as traumatic and neoplastic conditions of the bulla, ear canal and pinna. The complexity of these interventions can range from very basic to highly complex and ear surgery remains an area of soft tissue surgery that is associated with significant morbidity. In order to perform some of the more advanced surgeries an in depth knowledge of regional anatomy is vital. The cartilaginous ear canal is made up of the pinna, which is supported by the auricular cartilage. The pinna is continuous with the vertical canal, which then becomes more perpendicular to the skull base and continues as the horizontal canal. The annular cartilage fuses with the auricular cartilage but during dissection of the ear canal an obvious step can be appreciated between these two cartilages. The annular cartilage attaches to the skull at the external acoustic meatus, which forms the entrance to the tympanic bulla and is the insertion site of the tympanic membrane. The arterial supply to the external ear comes from a branch of the external carotid artery and venous blood drains to the maxillary vein. The retroarticular vein lies just rostral to the external auditory meatus and can easily be damaged during dissection. When this occurs it can be challenging to grasp and cauterize or ligate the vessel due to limited accessibility. Sustained packing of the area in combination with placement of a topical hemostatic agent such as an absorbable gelatin sponge is usually successful in stopping the hemorrhage. Several important neurological structures lie within the surgical field especially when total ear canal ablation is performed and neurological complications are the most common group of complications associated with ear surgery. Axons from postganglionic sympathetic neurons course close to the wall of the middle ear in dogs and cats and are particularly exposed in cats during curettage of the tympanic bulla during TECA-BO surgery. Damage to these fibers can result in Horners syndrome. The facial nerve exits the stylomastoid foramen immediately caudal to the external auditory meatus and then travels ventrally and cranially around the aspect of the tympanic bulla. The entrance to the inner ear at the epitympanic recess lies on the dorsomedial aspect of the tympanic bulla. Signs of vestibular disease can result in damage to the structures of the inner ear if over-exuberant curretage occurs in this area or if a fracture is propagated into the this area during bulla osteotomy. It is important to remember that unlike dogs who in general have one compartment to the bulla, the feline tympanic cavity consists of two compartments, a larger ventromedial and a smaller craniolateral compartment which are separated by a bony septum. It is imperative to penetrate both cavities of the bulla in cats as disease is usually not limited to one cavity.

Surgery of the pinna Occasionally traumatic lesions may require resection of a portion of the pinna if devascularization and necrosis of a portion of the pinna has occurred. However, more commonly pinnal surgery is indicated for treatment of neoplastic lesions. The most common neoplasm involving the pinna is squamous cell carcinoma. These lesions are particularly common in cats that lack pigment in their pinnae. These cats have been shown to have a 13.4x greater risk of developing SCC compared to those cats with pigmented pinnae.1 In cases where SCC is present a complete pinnectomy is often required to achieve a clean surgical margin. Pinnectomy is a simple procedure that involves a full-thickness incision medially and laterally that penetrates through the auricular cartilage. The skin margins which have a tendency to retract away from the cartilage are primarily sutured and healing in most cases is uneventful as long as the patient is prevented from self-traumatizing the area. The prognosis for cats with SCC of the pinna is good with one study documenting a disease free interval and median survival time of 681 and 799 days respectively.2

Surgical management of otitis externa Cases that have become refractory to medical management or animals that have such severe canal stenosis or obstruction that medical management can no longer be administered are surgical candidates. A variety of surgical procedures have been described over the years for otitis externa including lateral wall resection (Zepp procedure), vertical canal ablation, subtotal ear canal ablation with bulla osteotomy (STECA-BO) and total canal ablation with bulla osteotomy (TECA-BO). Lateral wall resection is the simplest of these procedures but has become seemingly less popular in recent years and is only indicated in patients that lack significant disease in their horizontal canals. After an initial skin incision is made over the lateral aspect of the vertical canal, dissection down to the cartilage is performed. The cranial and caudal margins of the lateral vertical ear canal are incised in order to create a cartilaginous flap. The flap is turned ventrally and sutured to the ventral margin of the skin incision in order to create a cartilaginous drainage board. The procedure does not remove any of the diseased cartilaginous canal but merely has the potential to improve access for administration of medications and can change the microenvironment of the ear canal by improving ventilation, and reducing humidity thus discouraging bacterial growth. However, results of this surgery have been disappointing with 635

one study reporting an unacceptable surgical outcome in 55% of cases overall and in 86.5% of the cocker spaniels in which it was performed mainly due to progression of disease.3 Lateral wall resection may be used successfully for resection of small well- circumscribed non-malignant masses of the lateral aspect of the vertical canal although these lesions rare. Vertical canal resection is another procedure that has fallen out of favor for management of otitis externa. In this procedure the vertical canal is isolated by resecting in a circumferential fashion around the proximal aspect of the ear canal as is done in a total ear canal resection. Dissection is continued as close as possible to the cartilage of the vertical canal until the point where the horizontal canal starts. At this point the vertical canal is amputated and the margin of the epithelium of the ear canal is sutured to the skin to create a new external ear orifice that is located in a more ventral location. The remainder of the skin incision is closed routinely. Similarly to the lateral wall resection vertical canal ablation may be a useful technique for resection of small well-circumscribed benign masses emanating from the wall of the vertical canal. Stenosis of the small orifice that is created can occur and clipping of the hair around the orifice may be necessary to prevent obstruction of air flow. Stenosis can be minimized by creation of a small drainage board as is performed with the Zepp procedure. While both the lateral wall and vertical canal resection have the advantage of minimizing the risk of damage to the neurovascular structures located closer to the base of the ear canal and the tympanic bulla they have lost favor in the management of otitis due to their inability to remove all of the diseased tissue. TECA-BO and a recently reported modification termed the STECA-BO4 are generally more appropriate for most dogs with moderate to severe signs of otitis externa and media but do carry a higher risk of neurovascular complications. For many years it has been known that an ear canal ablation without bulla osteotomy would result in a high incidence of fistula formation after surgery.5 The importance of performing the osteotomy therefore cannot be overemphasized. The STECA-BO was recently described in 18 dogs as a potentially less invasive alternative to TECA-BO that also allows preservation of the proximal vertical canal with potentially better ear carriage.4 In a traditional TECA-BO surgery dissection of the entire vertical and horizontal canal is performed staying as close to the cartilaginous canal as possible. Facial nerve paralysis occurs in 13-36% of dogs depending on which study is quoted and is usually the result of excessive retraction of the nerve during the dissection.6 Transection of the nerve is also possible and usually occurs when tissue around the horizontal canal that remains attached to the perineural tissues is being removed with some force causing the nerve to be withdrawn in a traumatic manner. In most cases, however, where transection has not occurred, facial nerve paralysis is temporary. If function does not return the third eyelid commonly functions as a surrogate for lubrication of the eye during globe retraction although this does not occur in all cases and severe corneal ulceration with the loss of function can occur in extreme cases. In cats facial nerve paralysis has been described in 56% of TECA-BO cases post-operatively and was permanent in 28% of cases in one study.7 Horners syndrome is principally seen in cats and has been reported to occur in 42% of cats of which it was permanent in 14 percent.7 Although animals with Horners syndrome have obvious cosmetic changes that are readily visible to owners it generally does not appear to be associated with significant detriment to quality of life in the post-operative period. Vestibular dysfunction is thankfully the least common (3-8% incidence in dogs) of the neurological disorders seen in small animals after TECA-BO but has the most profound affect on quality of life in the post-operative period.6 Damage to the inner ear may occur due to overzealous curettage of the dorsomedial aspect of the bulla. The author has also seen this complication after fracturing of the bulla during the osteotomy procedure. When performing the bulla osteotomy it is advised that small pieces of bone be removed or that a burr be used. Significant pressure applied to rongeurs on larger pieces of bone can propagate fractures in the area of the petrous temporal bone that can result in vestibular dysfunction. Recovery from vestibular signs can be incomplete and can take several months. Fistula formation after TECA-BO is another potentially serious complication that can arise if any infected epithelium or canal tissue is not removed. The incidence of this complication is between 2-10% and treatment is usually limited to re-exploration of the surgical site as antibiotics are not usually successful in managing these infections.6 Re-exploration can be performed using either a ventral or lateral approach, the latter being chosen if remaining cartilage is detected on pre-operative advanced imaging studies which are recommended. However, owners should be aware that even after re-exploration recurrence of signs is possible.8

Surgical treatment of ear canal neoplasia Tumors of the ear canal are predominantly malignant in origin especially in cats. Ceruminous gland adenocarcinoma (CGA) is the most common tumor in cats and dogs with squamous cell carcinoma being almost as common as CGA in cats. Metastasis is uncommon, however, with spread to lymph nodes and lungs documented in less than 10% of cases.9 Total ear canal ablation is firmly established as the procedure of choice for malignant ear canal tumors to provide the best long-term control of local disease. In dogs with malignant ear canal tumors median survival time has been documented to be 58 months.9 Cats with CGA have a median survival time of 49 months. However, survival time for those cats with SCC was only 3.8 months in one study.9

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References 1) Dorn CR, Taylor DON, Schneider R. Sunlight exposure and risk of developing cutaneous and oral squamous cell carcinoma in white cats. J. Nat Cancer Inst 1971;46:1073-1078 2) Lana SE, Ogilvie GK, Withrow SJ et al. Feline cutaneous squamous cell carcinoma of the nasal planum and the pinnae: 61 cases. J Am Anim Hosp Assoc 1997;33:329-32. 3) Sylvester AM. Potential factors affecting dogs with a resection of the lateral wall of the vertical ear canal. Can Vet J 1998;39:157-160 4) Matthews KG, Hardie EM, Marcia Murphy K. Subtotal ear canal ablation in 18 dogs and one cat with minimal distal ear canal pathology. J Am Anim Hosp Assoc. 2006;42:371-380 5) Smeak DD, DeHoff William D. Total ear canal ablation. Clinical results in the dog and cat. Vet Surg 1986;15:161-170 6) Smeak DD. Management of complications associated with total ear canal ablation and bulla osteotomy in dogs and cats. Vet Clin Small Anim 2011;41:981-994 7) Bacon NJ, Gilbert RL, Bostock DE et al. Total ear canal ablation in the cat: indications, morbidity and long-term survival. J Small Anim Pract. 2003;44:430-434. 8) Holt D, Brockman DJ, Sylvestre AM et al. Lateral exploration of fistulas developing after total ear canal ablations: 10 cases (1989-1993). J Am Anim Hosp Assoc 1996;32:527-30 9) London CA, Dubilzeig RR, Vail DM et al. Evaluation of dogs and cats with tumors of the ear canal: 145 cases (1978-1992). J Am Vet Med Assoc 1996;208:1413-1418

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Gall Bladder Mucoceles: The Kiwi Inside Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

Gall bladder mucocele (GBM) may currently represent the most common indication for surgical management of extra-hepatic biliary tract disease in dogs. It has not yet been convincingly described in cats. The underlying lesion has been described as cystic mucosal hyperplasia.1 Hypersecretion of mucus progressively leads to an accumulation of gelatinous bile within the gall bladder lumen. Increased viscosity over a period of weeks or months leads to thick gelatinous material eventually occupying the entire lumen of the gall bladder and in some cases also being present in the common bile duct. This can in some cases lead to clinico-pathological signs consistent with extra-hepatic biliary obstruction. In other cases eventual gall bladder rupture may occur possibly secondary to increases in intracholic pressure and/or gall bladder wall infarction. This will lead to an initial localized and progressively more generalized bile peritonitis.

Etiopathogenesis The cause of GBM remains largely unknown but recent reports have shown associations (although not a causative link) between GBM and certain intercurrent disease processes with a focus on endocrinopathies and other metabolic abnormalities. Certain genetic predispositions may play a role as Shetland Sheepdogs were recently shown to be predisposed to gall bladder disease albeit not specifically to GBM formation.2 Several previous studies have commented anecdotally on the relatively high incidence of endocrinopathies that are present in dogs with GBM.2-4 In a recent report evaluating a possible association between GBM and hyperadrenocorticism (HAC) and hypothyroidism (HT) both conditions were found to have an association with GBM.5 Dogs diagnosed with HT were 3.0 times more likely to have GBM than dogs without HT and the odds of having a mucocele in dogs with HAC was 29.0 times greater than dogs without HAC. In all 21% of dogs with GBM had HAC compared to 2% in the control group. In the case of HT 14% of GBM dogs had the condition compared to 5% in the control group. Certain limitations were present in this study and no causal relationship can be proven from this data.5

Diagnosis A combination of clinical signs, laboratory parameters and imaging studies are used in the diagnosis of GBM. The most frequent laboratory abnormalities include elevations of alanine aminotransferase (ALT), alkaline phosphatase (ALKP), and aspartate aminotransferase (AST). Serum bilirubin is elevated in most cases but is often normal in early cases. A leukocytosis is present in half of the cases. Abdominal radiographs can be helpful but are often non-specific. Hepatomegaly may be evident and gall bladder enlargement with partial mineralization of contents is an occasional finding. Abdominal ultrasonography is the most useful imaging study for this condition. The gall bladder usually contains echogenic material with a typical stellate or finely striated bile pattern (kiwi fruit) which differs from biliary sludge by the absence of gravity dependant bile movement.6 Gall bladder rupture is suggested by gall bladder wall discontinuity, the presence of pericholecystic hyperechoic fat or an accumulation of fluid in the abdomen. The sensitivity of ultrasound for gall bladder rupture is 85.7%, so in most cases a suspicion of biliary peritonitis should be ruled out by abdominocentesis or diagnostic peritoneal lavage.7

Management Appropriate management of gall bladder mucoceles depends on clinical presentation. The successful medical management of two dogs with GBM that were followed ultrasonographically has been reported.8 Medications administered included ursodiol, S-adenosyl methionine and famotidine although the relative role of these drugs in the resolution of the GBM can only be hypothesized.8 The belief that most mucoceles should be treated surgically is probably justified by the high levels of morbidity and mortality seen in cases that develop EHBO or bile peritonitis secondary to gall bladder rupture.4,7 However, medical management can be considered in early cases that have significant co-morbidities and are poor anesthetic candidates. Further research into the medical management of GBM seems warranted by this report. In most other cases the procedure of choice for GBM is cholecystectomy although one report includes a description of a significant percentage of dogs that underwent biliary rerouting procedures.4 Most dogs with GBM do not have gall bladders that remain healthy enough to allow a viable cholecystoduodenostomy to be performed and progressive gall bladder wall necrosis has been reported.4 It is generally considered that the gall bladder wall is the source of excessive mucus production and so the underlying cause appears to be removed when a cholecystectomy is performed. The gall bladder should always be submitted for histopathological analysis and a sample of the bile and a portion of the gall bladder wall should be submitted for bacterial culture and sensitivity testing. Evidence is somewhat conflicting as to whether infection is common in cases of biliary mucoceles with positive cultures for aerobes and anaerobes being reported in 9-75% and 0-25% respectively.4,6,7 Enterococcus and E.Coli isolates are the most frequently cultured bacteria. 638

Gall bladder rupture with subsequent bile peritonitis is encountered in 23-60% of cases and surgeons should be prepared for this eventuality.3,4,6 Some form of ongoing drainage is helpful in many cases and can consist of closed suction drainage using Jackson- Pratt drains or open abdominal drainage post-operatively. In dogs with GBM and concurrent evidence of partial or complete EHBO, such as ultrasonographic common bile duct distension or hyperbilirubinemia it is important to ensure that the common bile duct is free of congealed gall bladder mucus post-operatively. Concurrent EHBO has been documented in up to 30% of cases and based on laboratory data alone functional obstruction may be present in an even higher percentage of cases.4,7 Ensuring bile duct patency intraoperatively by catheterization and flushing as outlined above is critical especially in patients that have laboratory or imaging evidence of EHBO as persistent obstruction post-operatively may result if this is not performed. The treatment of incidentally discovered or asymptomatic mucoceles is controversial. Care must be taken to avoid confusing early mucocele formation with the presence of biliary sludge ultrasonographically, a common incidental finding in dogs and cats. A careful history should also be taken in these cases as some apparently asymptomatic dogs will have mild to moderate clinical signs attributable to the presence of GBM, which can resolve after cholecystectomy.9 No controlled studies exist to compare surgical and conservative management of incidentally discovered mucoceles and so each case must be considered on its own merit. Recently the development of a laparoscopic cholecystectomy technique in dogs and its application to the treatment of gall bladder mucoceles has been described and may be a good option for dogs with incidentally diagnosed mucoceles.9

Prognosis The prognosis for GBM is generally favorable especially if treated early and no bile leakage or trauma to the biliary tract is present. Post-operative complications consist of further leakage of bile from the surgery site, pancreatitis and re-obstruction of the common bile duct with gelatinous bile post-operatively. Most dogs that survive the perioperative period will not have long-term recurrence or complications. Overall perioperative mortality in the veterinary literature ranges from 22-32%.4,7

References 1. Kovath RM, Hildebrandt PK, Marcus LC: Cystic mucinous hypertrophy of the mucosa of the gall bladder in the dog. Vet Pathol 2:574-584, 1965. 2. Aguirre AL, Center SA, Randolph JF, et al: Gallbladder disease in Shetland sheepdogs: 38 cases (1995–2005). J Am Vet Med Assoc 231:79-88, 2007. 3. Mehler SJ, Mayhew PD, Drobatz KJ, et al: Variables associated with outcome in dogs undergoing extrahepatic biliary surgery: 60 cases (1988– 2002). Vet Surg 33:644-649, 2004. 4. Worley DR, Hottinger HA, Lawrence HJ: Surgical management of gallbladder mucoceles in dogs: 22 cases (1999–2003). J Am Vet Med Assoc 225:1418-1422, 2004. 5. Mesich ML, Mayhew PD, Paek M, et al: Gallbladder mucoceles and their association with endocrinopathies in dogs: a case control study. J Sm Anim Pract 50:630-635, 2009. 6. Besso JG, Wrigley RH, Gliatto JM, et al: Ultrasonographic appearance and clinical findings in 14 dogs with gall bladder mucocele. Vet Radiol Ultrasound 41:261-271, 2000. 7. Pike FS, Berg J, King NW, et al: Gall bladder mucocele in dogs: 30 cases (2000–2002). J Am Vet Med Assoc 224:1615-1622, 2004. 8. Walter R, Dunn ME, d’Anjou MA, et al: Nonsurgical resolution of gallbladder mucocele in two dogs. J Am Vet Med Assoc 232:1688-1693, 2008. 9. Mayhew PD, Mehler SJ, Radhakrishnan A: Laparoscopic cholecystectomy for management of uncomplicated gall bladder mucocele in six dogs. Vet Surg 37:625-630, 2008.

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Thyroid and Parathyroid Surgeries Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

Therapeutic strategies for management of thyroid and parathyroid tumors have evolved significantly over the last decade in some areas and are little changed in others. To obtain the best outcomes in surgical diseases of the thyroid and parathyroid glands a thorough knowledge of the biological behavior of the different tumors is required as well as an appreciation of the regional anatomy.

Regional anatomy The thyroid glands lie in the proximal neck region on either side of the trachea and in close association with several structures that must be protected during therapeutic procedures. The glands lie medial and ventral to the carotid sheath which contains the carotid artery, internal jugular vein and vagosympathetic trunk. The recurrent laryngeal nerve lies on the dorso-lateral aspect of the trachea and is therefore dorsomedial to the thyroid glands. The recurrent laryngeal nerve is a very fine structure, which in smaller animals can be challenging to visualize. The blood supply to both thyroid and parathyroid glands comes principally from the cranial thyroid artery, which is a branch of the carotid artery. A caudal thyroid artery contributes blood supply to the glands in dogs but is lacking in most cats. Venous drainage occurs through the cranial and caudal thyroid veins which drain to the internal jugular vein. There are four parathyroid glands, two of which are extracapsular and two of which are intracapsular. The exact location can be quite variable but generally the extracapsular glands lie within the fascia at the cranial pole of the thyroid gland and are usually easier to visualize as small tan spherical bodies. The intracapsular glands lie approximately half way down the thyroid gland deep to the capsule and on the medial aspect of the thyroid. Ectopic thyroid and parathyroid tissue can be present in both dogs and cats and is an important consideration when considering therapeutic strategies. In dogs the incidence of ectopic thyroid tissue is less well documented but neoplastic transformation of ectopic thyroid tissue has been documented in both dogs and cats. Predilection sites for ectopic thyroid neoplasia in dogs appear to be at the base of the tongue or hyoid apparatus1 or in the cranial mediastinum.2 In cats hyperfunctional ectopic adenomatous hyperplasia occurs in up to 20% of hyperthyroid cats although malignant transformation has not been as well described.3 Ectopic parathyroid tissue is rare in dogs occurring in only 3-6% of dogs and is usually associated with the thymus. In cats, ectopic parathyroid tissue is much more common occurring in approximately 35-50% of cats.

Thyroid gland – Comparative oncology Dogs and cats both suffer from benign as well as malignant disease of the thyroid gland with benign disease predominating in cats and malignant disease predominating in dogs. Approximately 90% of dogs with a palpably enlarged thyroid gland will have a thyroid carcinoma and in most cases these will be surgically resectable. Only about 10% of these tumors are functional creating a hyperthyroid state similar to that seen in cats with hyperthyroidism. Metastasis at the time of surgery has occurred in 35-45% of cases at the time of diagnosis with the lungs and local lymph nodes being the most common sites affected. Retropharyngeal lymph nodes are one of the primary drainage nodes for the thyroid glands. Tumor size is predictive of metastatic rate with larger tumors having higher metastatic rates at diagnosis. The prospective thyroid surgeon should be aware that substantial thyroid neovascularization is the norm in thyroid carcinomas and that profuse hemorrhage is very possible during surgery. Patients should ideally be cross-matched and typed prior to surgery. Due to the proximity of important neural structures we always use bipolar electrosurgery close to the gland and the primary goal of therapy is removal of the entire tumor without penetration of the capsule. The ability to preserve parathyroid gland function is preferable but not usually possible. In unilateral cases this is generally not important due to the ability of the contralateral gland to maintain the euthyroid state. However in bilateral cases post-operative hypoparathyroidism is a greater concern and occurred in 11/15 dogs in one study of dogs undergoing bilateral simultaneous thyroidectomy.4 Laryngeal paralysis has also been seen as a complication after thyroid carcinoma resection although is also more likely to be a clinically relevant problem in bilateral cases. Despite the high propensity for metastatic spread at the time of diagnosis canine thyroid carcinomas have a good prognosis even without chemotherapy in some cases. Prognosis for dogs with thyroid carcinoma is generally quite good with median survival times reported of around 3 years for mobile tumors and 6-12 months for invasive masses. Invasive tumors that are immobile or invading underlying structures are uncommon and may necessitate other non-surgical treatment strategies. External beam irradiation of invasive thyroid carcinoma has been associated with very reasonable outcomes in one study demonstrating progression-free survival rates of 80% and 72% at 1 and 3 years respectively.5 I131 therapy may also be used for treatment of dogs with non-resectable tumors with success.6 The use of adjuvant chemotherapy has never been shown to be highly effective in thyroid carcinoma. One recent study suggested that the addition of chemotherapy did not have a beneficial effect on survival (median survival of dogs undergoing surgery and chemotherapy was 518 days compared to 510 days for surgery alone) although this was a study of only 44 dogs.7 Ectopic thyroid carcinomas have been described in several studies with two main predilection sites emerging, the cranial mediastinum and the ventral laryngeal area. A series of nine dogs with cranial mediastinal carcinomas has been described of which 640

five were thyroid in origin.2 Despite being amenable to surgical resection in many cases these tumors can be locally invasive and perioperative morbidity can be high when surgical resection is considered. A recent report describes the imaging findings associated with 8 dogs that presented with invasive ectopic thyroid carcinomas centered around and invasive into the basihyoid bones.1 While these often highly vascular masses may be amenable to surgical debulking their invasiveness may preclude a clean margin of resection being attainable and treatment with radiation therapy may be preferable. The vast majority of thyroid lesions in cats are associated with adenomatous hyperplasia and are detected due to their propensity to overproduce thyroid hormone with the resulting symptoms of weight loss, polyphagia and polydispsia amongst others. In the authors practice these cats are almost exclusively treated using I131 therapy although surgical thyroidectomy using a modified extracapular technique has been reported to have excellent results in experienced hands.8 In 1-3% of hyperthyroid cats, however, a thyroid carcinoma is present and this should be suspected in cases where the mass is larger than expected, if the T4 concentration is very high, if there has been a poor response to therapy or if distant metastasis is present.9,10 The scintigraphic pattern of radionuclide uptake has been evaluated in cats but is not a reliable indicator of malignancy.10 Feline thyroid carcinoma has been treated with surgical thyroidectomy and I131 therapy. I131 therapy has been shown to be associated with very prolonged survival (median 814 days, range 181-2381) in one small case series in which no cats suffered a recurrence of hyperthyroidism during the follow-up period.10 I131 has the advantage of treating all thyroid tissue including ectopic deposits although 3-10 fold increases in I131 dose are required to treat thyroid carcinoma compared to benign disease which can cause problems with radiation safety protocols.10

Parathyroid gland – Comparative oncology Both benign and malignant disease of the parathyroid glands have been reported in both dogs and cats and are a common entity in small animal practice. Functional parathyroid adenomas that lead to hypocalcemia are especially common and in 90% of dogs are solitary lesions with the remainder usually having two lesions. Adenomas can reside in any one of the four glands and careful inspection at the time of surgery is necessary to diagnose these often small (most commonly 3-10 mm) masses. They present as small raised nodules that upon digital palpation appear firmer than the surrounding thyroid tissue. The clinical picture can sometimes be confused by the presence of non-neoplastic chronic change within adjacent thyroid glands in some dogs. Fine dissection is used along with bipolar electrosurgical units to delicately resect the offending mass. Several surgical options can be considered intraoperatively for adenoma resection. An enucleation of the mass with the aim of not penetrating the parathyroid capsule (with the consequent risk of leaving behind neoplastic cells) can be successful when resecting the extracapsular glands. The internal gland is usually removed using a parathyroidectomy with partial thyroidectomy approach. This author usually performs the thyroid transection with bipolar electrosurgery being careful to preserve the blood supply to the cranial pole of the thyroid where the external parathyroid gland resides. In cases where multiple masses are present on one side or if a malignancy is suspected a complete thyroid/parathyroidectomy is recommended with ligation of both cranial and caudal thyroid arteries and veins. Assuming the contralateral glands are unaffected post-operative hypocalcemia should not be a long-term problem. Intraoperative monitoring of PTH has been described to aid in confirmation of excision of all adenomatous tissue.11,12 In one study of nine clinical cases significant drops in PTH occurred in all dogs after excision of the mass. However, in another study significant drops occurred in PTH level after resection of only one of two affected masses suggesting that this test may lack specificity.11 Parathyroid ablative techniques are also frequently performed in the author’s institution for treatment of benign parathyroid adenomas. Ethanol ablation was performed initially but was associated with a higher level of recurrence of hypercalcemia. More recently radiofrequency ablation has been used with results very similar to those of surgical parathyroidectomy and long-term control of hypercalcaemia in dogs of approximately 90%.13,14 Post-operative hypocalcemia is the principal post-operative complication of parathyroidectomy or parathyroid ablation. Dogs with prolonged pre-operative hypercalcemia and those with very high pre-operative ionized calcium levels have traditionally been considered at high risk for this complication, which is clinically significant in approximately 33% of post-operative patients although two recent studies were unable to confirm these risk factors for post-operative hypocalcemia.15,16 Primary hyperparathyroidism is very rare in cats with only approximately 20 cases reported. In this species post-operative hypocalcemia appears to be less of a problem with symptoms of hypocalcemia not seen in any cat despite hypocalcemia being reported on the biochemical screen. Some cats with primary hyperparathyroidism have been reported with parathyroid carcinoma although resection appeared to be associated with excellent long-term control of hypercalcemia also. Malignant disease of the parathyroid glands can also be a cause of hypercalcemia in dogs and it is estimated to account for 4-7% of parathyroid nodules in this species. A recent study reported that parathyroidectomy alone can provide excellent control of parathyroid carcinomas with no recurrence of hypercalcemia documented in this cases series of dogs that were treated by parathyroidectomy with or without ipsilateral thyroidectomy.17

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References 1) Rossi F, Caleri E, Bacci B et al. Computed tomographic features of basihyoid ectopic thyroid carcinoma in dogs. Vet Radiol Ultrasound 2013;54:575-581 2) Liptak JM, Kamstock DA, Dernell WS et al. Cranial mediastinal carcinomas in nine dogs. Vet Comp Oncol 2008;6;19-30 3) Harvey AM, Hibbert A, Barrett EL et al. Scintigraphic findings in 120 hyperthyroid cats. J Fel Med Surg 2009;11:96-106 4) Tuohy JL, Worley DR, Withrow SJ. Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). J Am Vet Med Assoc 2012;241:95-103 5) Theon AP, Marks SL, Feldman ES et al. Prognostic factors and patterns of treatment failure in dogs with unresectable differentiated thyroid carcinomas treated with megavoltage irradiation. J Am Vet Med Assoc 2000;216:1775-1779 6) Turrell JM, McEntee MC, Burke BP et al. Sodium iodine I131 treatment of dogs with nonresectable thyroid tumors: 39 cases(1990-2003). J Am Vet Med Assoc 2006;229:542-548 7) Nadeau ME, Kitchell BE. Evaluation of the use of chemotherapy and other prognostic variables for surgically excised canine thyroid carcinoma with and without metastasis. Can Vet J 2011;52:994-998 8) Naan EC, Kirpensteijn J, Kooistra HS et al. Results of thyroidectomy in 101 cats with hyperthyroidism. Vet Surg 2006;35:287-293 9) Turrel JM, Feldman EC, Nelson RW et al. Thyroid carcinoma causing hyperthyroidism in cats: 14 cases (1981-1986). J Am Vet Med Assoc 1988;193:359-364 10) Hibbert A, Gruffydd-Jones T, Barrett EL et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. J Fel Med Surg 2009;11:116-124 11) Ham K, Greenfield CL Barger A et al. Validation of a rapid parathyroid hormone assay and intraoperative measurement of parathyroid hormone in dogs with benign naturally occurring primary hyperparathyroidism. Vet Surg 2009;38:122-132 12) Graham KJ, Wilkinson M, Culvenor J et al. Intraoperative parathyroid hormone concentration to confirm removal of hypersecretory parathyroid tissue and time to post-operative normocalcemia in nine dogs with primary hyperparathyroidism Aust Vet J 2012;90:203-209 13) Pollard RE, Long CD, Nelson RW et al. Percutaneous ultrasonographically guided radiofrequency heat ablation for treatment of primary hyperparathyroidism in dogs. J Am Vet Med Assoc 2001;218:1106-1110 14) Rasor L, Pollard R, Feldman EC. Retrospective evaluation of three treatment methods for primary hyperparathyroidism in dogs. J Am Anim Hosp Assoc 2007;43:70-77 15) Arbaugh M, Smeak D, Monnet E. Evaluation of preoperative serum concentrations of ionized calcium and parathyroid hormone as predictors of hypcalcemia following parathyroidectomy in dogs with primary hyperparathyroidectomy: 17 cases (2001-2009). J Am Vet Med Assoc 2012;241:233- 236 16) Milovancev M, Schmiedt CW. Preoperative factors associated with postoperative hypocalcemia in dogs with primary hyperparathyroidism that underwent parathyroidectomy: 62 cases (2004-2009). J Am Vet Med Assoc 2013;242:507-515 17) Swayer ES, Northrup NC, Schmiedt CW et al. Outcome of 19 dogs with parathyroid carcinoma after surgical excision Vet Comp Onc 2011, 10: 57- 64

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Gastric Dilation and Volvulus Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

Pathophysiology and risk factors Gastric dilation and volvulus (GDV) syndrome has always represented the quintessential surgical emergency faced by veterinarians. Attempts at elucidation of the pathophysiology of the condition remain challenging but a variety of predisposing factors have been documented including increased thoracic depth-to-width ratio, history of GDV in a first degree relative, eating one meal per day, small food particle size and eating rapidly. Breeds at high risk include Great Danes, Gordon and Irish Setters, Weimeraners, St Bernards, and Standard Poodles. Preoperative management Preoperative management of GDV is a well-studied science now and the importance placed on adequate hemodynamic stablization preoperatively cannot be overstated. Generally fluid resuscitation is performed with a combination of crystalloid and colloids with the overall aims to rapidly increase intravscular volume and then maintain intravascular volume by increasing oncotic pressure. Sodium chloride or lactated ringers solution can be administered at rates up to 90mls/kg in dogs although these fluid rates should be chosen based on an individual patients clinical parameters. Hydroxyethyl starch is usually used as a colloid at rates of 10-20 ml/kg. Decompression should be performed as soon as possible after admission and can be achieved using either orogastric intubation or percutaneous placement of an over-the-needle catheter. If orogastric tube placement is chosen the dog may be lightly sedated (this may not be necessary in cooperative dogs or those that are very sick) and a 2 inch roll of white tape placed between the incisiors. A large-bore orogastric tube is then placed through the roll of tape and passed down into the stomach (mark on the tube prior to use the length required to reach the last rib). Care should be taken as the tube passes into the stomach not to cause further compromise to the distal esophagus or stomach. Stomach contents will usually rapidly be evident draining in the tube which is then held over a bucket until no further stomach contents are obtained. If the use of an orogastric tube fails or cannot be passed into the stomach then a large- bore catheter can be passed into the stomach over the site of greatest gastric tympany after aseptic preparation of the skin.

Surgical treatment Once in the operating room a standard ventral midline celiotomy is performed. Immediately upon entry into the peritoneal cavity inspection of the surface of the stomach will reveal whether a volvulus is currently present. If the superficial leaf of the greater omentum is draped over the stomach it generally means that a volvulus has occurred as when the greater curvature of the stomach is twisted ventrally and over to the left side it drags with it the greater omentum confirming the presence of volvulus. The stomach at this stage may have been well-decompressed pre-operatively in which case derotation can be performed or it may have refilled with a substantial amount of gas between the time of decompression and the time it took to begin the celiotomy. Derotation is facilitated by decompression and so needle decompression performed by inserting an 18-gauge needle into a healthy area of gas-distended stomach wall and attaching wall suction to the needle is generally an efficient way to perform rapid intraoperative decompression. Once the stomach has been decompressed derotation can be performed. Generally this is a simple maneuver that is facilitated by passing a surgeons hand down the left body wall lateral to the stomach and grasping the lesser curvature. This palpable “crease” in the stomach can be used as a handle as the stomach is rotated ventrally towards the right side to reposition the antrum on the right side and the fundus over to the left. Derotation might be facilitated by simultaneously pushing the fundus in a dorsal direction and over to the left side with the surgeons other hand as the antrum is being rotated ventrally. If there is ever confusion regarding the position of the stomach after derotation the surgeon should go back to basic anatomical principles by assessing the hiatal region and cardia to ensure that no twisting exists, ensuring that the fundus is located on the left hand side and confirming that the pylorus and descending duodenum are now correctly positioned along the right side of the body wall. The next step in intraoperative management is to assess the stomach for viability. It is imperative that the decision regarding stomach viability is made after decompression and derotation have been completed and this author will often delay the decision as to whether gastric resection is necessary until after a full exploratory celiotomy has been completed. The reason for this is that until the ingastric pressure has been relieved it can be challenging to assess the margins of necrosis and a highly distended stomach may appear more ischemic than it really is once that pressure has been relieved. The decision to resect stomach still largely relies on some very basic factors that include the color, consistency and perfusion of the stomach wall. Despite techniques such as laser doppler flowmetry1 and intravenous fluorescein2 having been used to assess wall viability these techniques are not generally practical in the clinical setting and so have never been widely adopted. Having said that the use of the factors mentioned, in the authors experience, provides a very good assessment of viability and this improves with experience. Areas of stomach that are black, green or very dark red are generally ischemic and need to be resected. Areas that are an intense red or have patchy areas of darker red are more challenging to interpret. In general color should be interpreted in conjunction with consistency. Any areas that are judged to be thin-walled are usually unhealthy and need to be resected. Thickened areas of 643

stomach wall are often edematous which usually means that blood supply to these areas remains and they may be salvageable. Once the surgeon has decided that gastric resection is necessary and the extent to which he/she will resect the stomach a decision must be made as to whether to use a hand-sewn technique or one involving surgical staplers if they are available. Firstly the entire area around the stomach should be packed off liberally with moistened sponges to avoid contamination in the event of spillage of gastric contents. The use of surgical staplers in experienced hands is probably quicker but increases costs associated with the technique. If using the gastrointestinal stapler (GIA), the appropriate staple size should be chosen which is usually the 4.8mm leg length staples. In many cases the use of two cartridges might be necessary to bridge the entire length of the portion of stomach to be resected.3 The GIA stapler has the advantage of having 4 lines of staples and a blade that cuts between them thus sealing both sides of the stomach and minimizing spillage of gastric contents. However, many surgeons advocate oversewing of the staple line after gastric stapling possibly diminishing the time advantage of the use of surgical staplers for this indication. The thoracoabdominal stapler (TA) can also be used for gastric resection with the one disadvantage that the TA stapler does not seal both sides of the stomach and so contamination from the resected portion of the stomach can occur. While stapled gastric resection has some advantages most surgeons probably still use a hand-sewn approach, which is perfectly acceptable for this purpose. When using a hand-sewn approach the area is again packed off with moistened sponges and stay sutures are placed circumferentially approximately 1cm from the planned margin of resection. With assistants providing constant upward tension on the stay sutures to avoid gastric spillage the surgeon starts to incise the stomach. At this point bleeding from the mucosal and seromuscular layers of the stomach can be assessed and if deemed adequate the apposing margins of gastric mucosa are closed in a simple continuous pattern using a monofilament absorbable suture material (usually polydioxanone). This author usually progresses by incising a few centimeters and then suturing a few centimeters and repeating that pattern until the entire ischemic section of the stomach has been excised and the mucosal layer has been closed. At that point a second layer of sutures are placed in the seromuscular layer of the stomach in a continuous cushings or lembert pattern to over sew that layer. Upon incising of the stomach in some dogs with GDV the surgeon will note that despite a seromuscular layer that appears pink/red and is bleeding readily the mucosa may be ischemic or even black in color. The gastric mucosa has a much higher metabolic rate and is more sensitive to perfusion impairment caused by the increased wall tension that occurs in these cases and so differential ischemia of gastric wall layers can occur. If mucosal ischemic is only slightly more extensive that seromuscular ischemia the non-viable mucosal section can be included in the resection. However, the author has seen cases where mucosal ischemia was very extensive and in these cases it may be necessary to leave the ischemic mucosa in and rely on a healthy seromuscular wall to heal the stomach with an assumption that mucosal sloughing and subsequent regeneration will occur in time. To date our experience with these cases has been positive and leaving the ischemic mucosa in place appears to be tolerated. The technique of gastric invagination was reported several years ago as an alternative to gastric resection with the purported advantage that it may reduce surgical time in patients with gastric necrosis secondary to GDV. Clinical reports of significant case numbers managed with this technique have not emerged but the literature includes a case where the site of gastric inversion sloughed to become a large linear bleeding ulcer post-operatively resulting in severe lethargy, anemia and melena.4 This technique is not performed by this author because of this concern and skepticism over whether this technique really provides a significant time saving. Once gastric resection, if necessary, has been completed the surgeon should turn their attention to ensuring that the remainder of the peritoneal cavity contains no further abnormalities as dogs with GDV not infrequently may exhibit comorbid conditions. When exploratory celiotomy has been completed a prophylactic gastropexy must be performed to minimize risk of recurrence. Risk of recurrence in the absence of prophylactic gastropexy is greater than 50% but is reduced to <5% if a gastropexy is performed.5 It is therefore likely that failure to perform a prophylactic gastropexy in GDV patients could expose the surgeon to legal liability. Many types of open surgical gastropexy have been described in dogs but in dogs with concurrent GDV the author only performs the very simple and rapid incisional gastropexy. This technique simply involves suturing the margins of two incisions created through the transversus abdominis of the stomach wall in the right cranial abdominal quadrant and a seromuscular incision created in the antrum of the stomach midway between the greater and lesser curvature. It is a highly reliable gastropexy that should almost guarantee that volvulus will not recur in the future (gastric dilation is still a life-long risk in these dogs). Post-operative management Post-operatively close attention needs to be paid to patient oxygenation, perfusion, cardiac rhythms and analgesia. Post-operative complications including aspiration pneumonia, disseminated intravascular coagulation, peritonitis, pancreatitis and ileus. Prophylaxis Prophylactic gastropexy in dogs at high risk of GDV is often performed and can be performed using open surgical techniques or laparoscopically. These include both laparoscopic-assisted techniques but are increasingly being performed using total laparoscopic techniques allowing the procedure to be performed in an ever more minimally-invasive way.

References 1) Monnet E, Pelsue D, MacPhail C: Evaluation of laser Doppler flowmetry for measurement of capillary blood flow in the stomach wall of dogs during gastric dilatation-volvulus. Vet Surg 35:198, 2006.

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2) Wheaton L, Thacker H, Caldwell S: Intravenous fluorescein as an indicator of gastric viability in gastric dilatation-volvulus. J Am Anim Hosp Assoc 22:197, 1986. 3) Clark GN, Pavletic MM. Partial gastrectomy with an automatic stapling instrument for treatment of gastric necrosis secondary to gastric dilation- volvulus. Vet Surg 1991;20:61-68 4) Parton AT, Volk SW, Weisse C. Gastric ulceration subsequent to partial invagination of the stomach in a dog with gastric dilatation-volvulus. J Am Vet Med Assoc 2006;228:1895-900 5) Glickman LT, Lantz GC, Schellenberg DB et al. A prospective study of survival and recurrence following the acute gastric dilation-volvulus syndrome in 136 dogs. J Am Anim Hosp Assoc 1998;34:253-9

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Rectal Tumors: The Good, the Bad, and the Ugly Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

Colorectal tumors are frequently encountered in small animal practice and can vary from simple to highly complex depending on their type, location and extent. In dogs the most frequently encountered lesions are adenomatous polyps followed by adenocarcinomas, Much less commonly plasma cell tumors, lymphoma, mast cell tumors and hemangiosarcomas can be seen. In cats the most common tumors are lymphoma and adenocarcinoma. Adenomatous polyps in dogs are well known to be pre-cancerous lesions that have the potential to undergo malignant transformation. Benign neglect of these tumors is therefore not recommended. Once invasion into the lamina propria and submucosa has occurred they are generally termed carcinoma in situ and once the basement membrane has been penetrated they are termed adenocarcinoma and at that stage are much more likely to metastasize. Most rectal tumors are either diagnosed due to the detection of hematochezia or fecal tenesmus or after a rectal examination has been performed. Less commonly, rectal masses may be evident after prolapsing out of the rectum. Other clinical signs seen in these patients can include dyschezia and weight loss. On rectal examination a palpable mass will be obvious in up to 60% of canine cases. Many epithelial tumors will ulcerate easily and so blood may be evident on rectal examination. Some cases with annular lesions may have a stricture-like area palpable. Diagnostic evaluation usually includes sampling of the mass by fine needle aspirate or biopsy as well as staging of the patient. Obtaining a sample for biopsy is very simple in those tumors that are located close to the anorectal junction. In these cases mucosal eversion will often yield sufficient access for aspiration, tru-cut biopsy or incisional biopsy. In cases where the lesion is located in the mid to proximal rectum, proctoscopy or colonoscopy may be required to secure a biopsy sample. It should be noted that in up to 30% of cases the results of endoscopic samples collected from colorectal masses do not agree with the histopathological results of definitive resections in one study.1 Staging of colorectal neoplasia should involve abdominal ultrasound and proctoscopy or colonoscopy to detect further lesions located more cranially within the colon. Ultrasound should detect metastatic spread to colic, hypogastric and medial iliac lymph nodes, liver or other organs. Thoracic radiographs should be performed to look for evidence of metastatic spread to the lungs. A knowledge of the regional anatomy and physiology is important to maximize success in management of colorectal tumors. In dogs blood supply to the rectum comes mainly from the cranial rectal artery, which is a branch of the caudal mesenteric artery. Every effort should be made to preserve this vessel although this is impossible during resections that involve the mid to cranial aspect of the rectum and very distal colon. In cats there is a greater contribution from the middle and caudal rectal arteries. One of the major potential complications of colorectal resections is the potential for fecal incontinence post-operatively. Two principal mechanisms can lead to fecal incontinence. Extensive damage to the external anal sphincter or the terminal 1.5cm of the rectum can lead to loss of voluntary continence. Loss of reservoir continence is also described and occurs due to loss of fecal storage ability. In a study using mixed breed dogs weighing 19-35kg when 6cm of rectum was resected using a dorsal approach all dogs were fecally incontinent post- operatively.2 This was not the case when either 0 or 4cm resections were performed.2 The authors hypothesized that this may be a reservoir issue or possibly a result of damage to the peritoneal reflection within which passes the important reflex arc to the pelvic plexus that provides the innervation to the rectum. It does seem vital that in any rectal resection the terminal 1-1.5cm of distal rectum be preserved in order to preserve continence. This has particular importance with regard to rectal pull-through where preservation of that segment may have a beneficial effect in preserving continence.3 The surgical approach to rectal lesions is largely dependant on the location and extent of the mass. A variety of surgical approaches have been used for management of colorectal tumors including the mucosal eversion technique,4 transanal endoscopic approach,5 the dorsal perineal approach,6 the rectal pull-through,3 combined abdominal-transanal pullthrough,3 and pelvic osteotomy techniques.7,8 Mucosal eversion is the simplest technique and is appropriate for small to moderate lesions (especially those that are pedunculated) in the distal rectum.4 A series of stay sutures can be used to evert the section of rectum that is of interest. Resection is followed by primary suturing of the defect in the rectal wall. The dorsal perineal approach has been used to gain access to the distal to mid-rectum for resections of modestly-sized lesions.5 An inverted U-shaped incision is made over the proximal aspect of the rectum. Dissection down onto the rectal wall is followed by resection and anastomosis. Rectal pull-through is classically indicated for lesions of the mid- to distal rectum although lesions more cranial can be resected with this technique if necessary.3,7 The technically challenging component of this technique is to find the dissection plane between the rectal wall and the external anal sphincter so that the sphincter is preserved as much as possible. The key, as mentioned, is to preserve the most distal 1-1.5cm of the rectum as this appears to decrease the likelihood of post-operative incontinence. A variation of the rectal pull-through for lesions that extend into the distal colon is to perform a combined abdominal-transanal pull-through.3 This advanced procedure is complex and involves mobilization of the intra-abdominal component prior to its exteriorization through a perineal approach. Finally the pelvic osteotomy techniques are

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potentially the most invasive and reserved for the most extensive lesions or lesions that are located within the cranial rectum/distal colon that would be difficult to approach from any of the perineal approaches.7,8 Two options exist here including a pubic symphysiotomy or a pubic-ischial osteotomy flap. Pubic symphysiotomy is technically less challenging but due to the limited ability to spread the pelvis apart, visualization is often less than ideal. The pubic-ischial osteotomy flap is more technically challenging but may provide much better surgical access to the pelvic rectum. The bone flap elevated using this technique is replaced after the rectal resection is completed and is either sutured or wired back into place.8 Complications after resection of colorectal tumors are commonplace especially with the more extensive lesions and more complex surgical procedures. The rectal pull-through is a relatively high morbidity surgery with complications including rectal bleeding, stricture formation, incisional dehiscence and wound infection as well as incontinence being reported with significant frequency.3

References 1. Valerius KD, Powers BE, Hutchison JM, et al: Adenomatous polyps and carcinoma in situ of the canine colon and rectum: 34 cases (1982–1994). J Am Anim Hosp Assoc 1997;33:156–160 2. Anderson GI, McKeown DB, Partlow GD et al. Rectal resection in the dog. A new surgical approach and the evaluation of its effect on fecal continence. Vet Surg 1987;16:119-125 3. Morello E, Martano M, Squassino C et al. Transanal pull-through rectal amputation for treatment of colorectal carcinoma in the in 11 dogs. Vet Surg 2008;37:420-426 4. Danova NA, Robles-Emanuelli JC, Bjorling DE. Surgical excision of primary canine rectal tumors by an anal approach in twenty-three dogs. Vet Surg 2006;35:337-340 5. Holt PE. Evaluation of transanal endoscopic treatment of benign canine rectal neoplasia. J Small Anim Pract 2007;48:17-25 6. Holt DE, Johnston DE, Orsher R et al. Clinical use of a dorsal surgical approach to the rectum. Comp Contin Educ Vet 1991;13:1519-1528 7. Aronson LR. Rectum, Anus and Perineum. In: Veterinary Surgery Small Animal (eds Tobias KM & Johnston SA), Elsevier Saunders, St Louis, MO, 2012, pp 1564-1600. 8. Yoon HY, Mann FA. Bilateral pubic and ischial osteotomy for surgical management of caudal colonic and rectal masses in six dogs and a cat. J Am Vet Med Assoc 2008;232:1016-1020

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Hernias of the Diaphragm: Traumatic, Pericardioiperitoneal, and Hiatal Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

Diaphragmatic hernias It is thought that up to 85% of diaphragmatic hernias (DH) are traumatic in origin and a significant proportion of dogs and cats that sustain major trauma can sustain DH. The theorized mechanism by which these injuries arise is by major blunt trauma to the abdomen with the glottis open causing a sudden increase in the pressure gradient between the chest and abdomen. Rupture of the diaphragmatic costal muscle is the most common consequence due to the inherent weakness of these tissues in comparison to the stronger central tendon. When costal muscles are involved tearing most commonly occurs parallel to the orientation of the costal muscle fibers and these are usually termed radial tears. Another common defect configuration is circumferential where the diaphragm is avulsed from its attachment to the body wall. Circumferential tears occur commonly in both dogs and cats but proportionally occur with greater frequency in cats.1,2 Almost any non-fixed organ within the abdominal cavity can become herniated in a DH but the most common include stomach, small intestine, liver, spleen. Of great importance prior to surgical intervention in DH cases is global assessment of the patient. Many cases of DH present with concurrent musculoskeletal or other organ system injuries. Recognition and treatment of comorbidities is essential in these cases and can in some cases distract the clinician from recognizing DH as well as other internal injuries. In one study only 57% of DHs were diagnosed within 30 days of trauma.3 Animals with DH should be carefully evaluated. In some cases no or few clinical signs referable to the respiratory system will be detected. In other cases mild to severe respiratory distress may be evident. Diagnostic assessment usually starts with thoracic radiography which should be performed with the least amount of physical restraint necessary. Classical signs consistent with DH include loss of a clear diaphragmatic outline and cranial displacement of abdominal organs or the presence of abdominal viscera within the thoracic cavity. Pleural effusion is evident in approximately 20% of cases.2,3 Ultrasonography has also been assessed as a diagnostic modality in these cases and was shown to have 93% accuracy in one report.4 Currently, the recommendation is that surgical intervention is warranted without delay after hemodynamic stabilization and treatment of other life-threatening injuries has been performed. Chronic diaphragmatic hernias are diagnosed frequently due to the sometimes delayed diagnosis in these cases.5,6 Despite concerns over these cases having a greater incidence of adhesion formation and re-expansion pulmonary injury, survival in chronic DH cases has not been shown to be different compared to those diagnosed shortly after injury. In one large study of 1674 cases mortality rates in dogs with acute and chronic DH were 27.8 and 26.2% whereas in cats those figures were 20% and 11.8% respectively.5 The surgical approach of choice for DH repair is a ventral celiotomy. Despite this, the possibility of having to perform a caudal sternotomy if significant adhesions exist in the chest should always be anticipated and so a wide clip and aseptic preparation of the entire thoracic area should be performed. Upon inspection of the diaphragmatic area, the defect is usually obvious. Herniated organs should be very gently grasped and caudal traction applied. In many cases organs will move easily out of the thoracic cavity back into the abdomen. In others, adhesions within the thorax or to the edges of the diaphragmatic defect may exist and can be broken down digitally or using electrocautery. In cases where traction does not result in abdominal organs retreating back into the abdomen two choices can be made. In some cases enlargement of the hernial defect may allow the hernial contents to become more mobile or may allow greater access to the adhesions. The other option is to perform a caudal sternotomy to provide the necessary visualization of intra-thoracic structures to allow hernial content reduction. Sternotomy was necessary in 28% of dogs and cats with chronic DH in one study.6 Once all hernial contents have been replaced in their correct anatomical location, closure of the defect is performed. In simple radial or circumferential tears where apposition of the edges can be performed without undue tension, primary apposition with either a simple interrupted or continuous line of 2-0 to 3-0 absorbable or non-absorbable suture is reasonable. The author favors not trimming the edges of the defect to minimize hemorrhage and maximize the suture holding power on tissue, which might be improved by anchorage around the scar tissue at the edge of the defect. In rare cases the defect in the diaphragm cannot be easily apposed in a tension-free manner and a reconstructive technique is required. This has been done using a large variety of different materials. The author usually favors an omentalized polypropylene mesh closure that is simple to perform and usually quite reliable. The peripheral 0.5cm of the mesh is turned over on itself and sutured to the muscular rim at the periphery of the defect using simple interrupted 3-0 non-absorbable monofilament sutures that pass through the double thickness of the mesh that has been turned over. The free cut end of the mesh is oriented towards the abdominal side to avoid the potentially sharp cut ends of the mesh damaging lung parenchyma. The abdominal component can then be covered with omentum to cushion the sharp edges as well as to cover the defect. Another elegant method of defect closure in chronic DHs with large defects is the use of a pedicled abdominal wall muscle flap from the tranversus abdominis.7 Just prior to final defect closure a catheter or red rubber tube can be inserted into the thoracic cavity and an acute drainage of air from the thorax can be performed making placement of an indwelling thoracic tube unnecessary in most cases. In cases where

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significant hemorrhage occurred during dissection or lung injury occurred or is suspected to have occurred, placement of an indwelling thoracic drain may be warranted. Some authors like to re-expand the lungs very slowly after DH repair to minimize the risk of re-expansion pulmonary edema. Placement of a thoracic drain that allows slow sequential thoracic drainage over time may be advantageous if this is of great concern. Re-expansion pulmonary edema appears to occur relatively rarely in these cases with few credible reports in the literature. However, if it occurs it can be life-threatening and so should be monitored for carefully in the post- operative period.

Pericardio-peritoneal diaphragmatic hernias PPDH results from the embryological failure of fusion within the most ventral aspects of the diaphragm. Communication between the pericardial sac and abdomen results although there is no communication into the thoracic cavity in these cases. Decision-making in PPDH management is controversial as many cases are asymptomatic and only detected on work-up of other conditions. In one study 41% of feline cases were detected incidentally and the abnormality occurs much more frequently in cats than dogs.8 Clinical signs that have been attributed to PPDH include signs of gastrointestinal and respiratory dysfunction as well as non-specific signs such as weight loss, anorexia and lethargy.8-10 Similarly to DH, organs most commonly herniated into the pericardial sac in PPDH cases include small intestine, liver and gall bladder.9 Thoracic radiography is sufficient for establishing the diagnosis in the vast majority of cats with classical signs including enlargement of the cardiac silhouette and visible abdominal viscera within the peritoneal sac. Cats with PPDH should always be evaluated for other congenital abnormalities such as pectus excavatum and other cardiac abnormalities which can be present in a proportion of cases. Decision making on surgical management has been controversial as many cats can experience long-term survival with medical management. Post-operative mortality in larger studies ranges from 5.1-14% of cases.8-10 However, left untreated progression of clinical signs or acute death have been documented. In one large study outcomes of the surgical versus conservative management appeared to be similar.10 However it is very likely that selection bias may affect outcomes in retrospective studies of this nature as the more clinically affected cases may be more likely to be treated surgically.10 Surgical treatment of PPDH involves reduction of the hernial contents back into the abdomen with subsequent closure of the diaphragmatic hernial defect. Adhesions of the liver and/or omentum to the epicardium can be encountered and these need to be very carefully broken down. The necessity for liver lobectomy to be performed needs to be considered if there is significant damage to liver lobes during reduction. Primary suturing of PPDH defects is possible in most cases.

Hiatal herniation In many cases the clinical signs of hiatal herniation are both vague and non-specific and diagnostic tests are plagued with the difficulties of imaging what is a dynamic and intermittent pathology. Hiatal herniation can occur in a number of different forms with four common types being recognized in veterinary patients. Type 1 is the sliding hiatal hernia and is the classical form seen in most patients who present just with intermittent regurgitation. It is associated with cranial movement of the gastroesophageal junction (GEJ) into the thoracic cavity and affects patients to varying degrees. Type 2 is much less common and is a paraesophageal hernia where part of the stomach moves into the thorax adjacent to the normal GEJ. Type 3 is a combination of the abnormalities seen in Type 1 and 2. Gastroesophageal intussusception is another abnormality that is not a true hiatal hernia but needs to be considered as a differential diagnosis in animals where these defects are suspected. In dogs it is known that the LES is a naturally lax structure compared to humans and that some gastro-esophageal reflux is normal in this species. What is not known is the relative contributions of muscular tone within the esophageal wall at the LES and the support afforded to the GEJ by the gastroesophageal ligament and crural muscles. It is known that in dogs with congenital or acquired sliding hiatal hernia the GEJ moves cranially and that in some normal dogs there may actually be no intra-abdominal component to the esophagus at all, meaning that the GEJ is located cranial to the diaphragm in those cases.11 Because of this inherent variation of normal in dogs as well as the lack of a complete understanding of the pathophysiology, diagnosis of the condition and interpretation of normal from abnormal can be challenging. The most common diagnostic test for HH used in clinical practice today is the positive contrast esophagram. Because of the dynamic nature of the disease these studies are best performed with the aid of fluoroscopy and even then there is probably a high rate of false-negative results. In our institution it is common practice to perform a second positive contrast esophagram if the first study is negative and the index of suspicion remains high for a diagnosis of HH based on signalment and clinical signs. Treatment of hiatal herniation is controversial as medical and surgical options exist. One study has suggested that 30 days of medical management may alleviate signs in many patients and should be pursued prior to surgical management. Surgical management using a combination of hiatal plication, esophagopexy and left fundic gastropexy is the classical combination of techniques used to treat HH but has never been extensively and objectively evaluated.12 Response rates in the range of 80% have been reported for this surgical regimen in the small numbers of cases reported.12,13

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References 1. Sullivan M, Reid J. Management of 60 cases of diaphragmatic rupture. J Small Anim Pract 1990;31:425-430 2. Garson HL, Dodman NH, Baker GJ: Diaphragmatic hernia: analysis of fifty-six cases in dogs and cats. J Small Anim Pract 1980;21:469 3. Wilson GP, Newton CD, Burt JK. A review of 116 diaphragmatic hernias in dogs and cats. J Am Vet Med Assoc 1971;159:1142-1145 4. Spattini G, Rossi F, Vignoli M et al. Use of ultrasound to diagnose diaphragmatic rupture in dogs and cats. Vet Radiol Ultrasound 2003;44:226-230 5. Downs DC, Bjorling DE. Traumatic diaphragmatic hernias: A review of 1674 cases. Vet Surg 1987;16:87 6. Minihan AC, Berg J, Evans KL. Chronic diaphragmatic hernia in 34 dogs and 16 cats. J Am Anim Hosp Assoc 2004;40:51-63 7. Helphrey ML: Abdominal flap graft for repair of chronic diaphragmatic hernia in the dog. J Am Vet Med Assoc 1982;181:791 8. Reimer SB, Kyles AE, Filipowicz DE et al. Long-term outcome of cats treated conservatively or surgically for peritoneopericardial diaphragmatic hernia: 66 cases (1987-2002) J Am Vet Med Assoc 2004;224:728-732 9. Banz AC, Gottfried SD. Peritoneopericardial diaphragmatic hernia: A retrospective study of 31 cats and eight dogs. J Am Anim Hosp Assoc 2010;46:398-404 10. Burns CG, Bergh MS, McLoughlin MA. Surgical and nonsurgical treatment of peritoneopericardial diaphragmatic hernia in dogs and cats: 58 cases (1999-2008) J Am Vet Med Assoc 2013;242:643-650 11. Pratschke KM, Fitzpatrick E, Campion D, et al: Topography of the gastro-oesophageal junction in the dog revisited: possible clinical implications. Res Vet Sci 76:171, 2004 12. Lorinson D, Bright RM. Long-term outcome of medical and surgical treatment of hiatal hernias in dogs and cats: 27 cases (1978-1996). J Am Vet Med Assoc 1998;213:381-384 13. Prymak C, Saunders HM, Washabau RJ. Hiatal hernia repair by restoration and stabilization of normal anatomy. An evaluation in four dogs and one cat. Vet Surg 1989;18:386-391

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Hemostasis and Electrosurgery: When to Use and What Where Philipp Mayhew, BVM&S, DACVS University of California Davis, CA

The use of electrosurgery (ES) in modern medicine dates back many years and a plethora of devices are in common usage today to aid in cutting and coagulating a variety of tissues. The technology behind ES remains to this day very poorly understood by most surgeons. Given the potentially harmful side effects of inappropriate use, it is prudent for at least a basic understanding of these technologies to be acquired. Currently many new options exist in ES that have revolutionized human surgery in recent years and are beginning to have the same effect in veterinary medicine. Electrosurgery is the use of radiofrequency alternating current to create heat in order to achieve dessication and protein coagulation. Wall outlets in North America create a 50-60Hz waveform, which is the frequency at which polarity changes per second in an alternating current. An ES generator will take this current and convert it into a higher voltage output in the range around 500kHz which is similar to that produced by an AM radio, hence the name radiofrequency. These higher frequencies are necessary as the lower frequencies can stimulate muscle and nerve cells to depolarize whereas the higher frequencies do not cause neuromuscular stimulation. Modern ES generators can also produce a variety of other different waveforms that will produce variations in the effect on tissues when they are applied. These changes include effects that promote “cutting” of tissue that are created using continuous relatively low-voltage waveforms. This waveform creates very high temperatures, vaporization, but little hemostasis. To create a “coagulation” effect an intermittent waveform is produced using high current density, which promotes hemostasis. There are also “blended” waveforms that create a combination of coagulation and cutting effects. The general principle is that a current released into tissues encounters impedance as it is passes through the tissue, which results in the generation of heat. Different tissues react differently to current and this is a function of impedance. Well-hydrated tissue such as muscle has the lowest impedance while dehydrated tissues such as scar tissue and fat will have higher impedance. The higher the impedance of the tissue, the higher the resistance to flow of current and the greater the temperature that is produced. Electrocautery, a term that is often used erroneously in place of ES, is the direct application of heat to tissues through direct tissue contact and results in denaturation of the tissue. However, electrocautery does not involve the creation of an electrical circuit and is rarely used in modern veterinary medicine. For current to pass through tissue an electrical circuit has to be created which must contain a positive and a negative pole so that ions and/or electrons can move between the two poles. Therefore all ES is really “bipolar” despite the common usage in medicine of the terms monopolar ES and bipolar ES. The difference between these two modalities lies in the location of the electrodes. In bipolar devices both electrodes are on the device tip resulting in current passing only a very short distance across the tips and exerting very precise effects on the small amount of tissue that is placed between the tips. In monopolar ES the device tip is one electrode and the second electrode is the grounding plate that is usually placed under the animals back.

Monopolar electrosurgery This form of ES is very efficient, allows tissue to be cut or coagulated very rapidly and decreases surgical time and blood loss. The main disadvantage in open surgery is the possibility of grounding pad burns. A large grounding pad is needed to disperse the current over a large area to avoid the temperature rising in the tissue over the area where it is placed. Therefore, if the base plate is incorrectly positioned or is only in contact with a relatively small area of the patient current concentration can result in thermal burns in these locations. There are now some grounding pads that incorporate a sensing system that alerts the user if grounding is inadequate. Vessels up to 2mm are effectively coagulated but dispersion of the current can cause burns up to 2cm away from the site of application.1 Monopolar ES can be used in minimally invasive surgery but it is potentially hazardous and so great care needs to be taken. A defect in the insulation of the instrument shaft can result in the passage of current to tissues that are not in the visual field resulting in iatrogenic injury. Direct coupling injuries can also occur when the instrument through which the electric current is passed comes into contact with the telescope, or other instrument, resulting in iatrogenic damage to tissues that may lie outside the visual field.

Bipolar electrosurgery Bipolar is generally considered somewhat safer than monopolar as the current only travels between the tips of the instrument and operates at lower power settings and voltage. It is therefore used preferentially when working in proximity to delicate structures such as large neurovascular bundles or spinal cord and brain tissue. Vessels up to 3mm can be effectively coagulated but must be carefully positioned between the tips of the device.

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Vessel-sealing devices Vessel-sealing devices are very helpful for hemostasis and simultaneously sealing and cutting a variety of tissues. They work by a combination of pressure exerted on tissue when the tissue is crushed in the tips of the device, followed by the application of bipolar or ultrasonic energy applied to the tissue. This process allows the elastin and collagen in the vessel wall to be sealed together permanently. They have been used for a variety of applications in veterinary medicine including open splenectomy as well as laparoscopic ovariohysterectomy, ovariectomy, cholecystectomy, adrenalectomy, thoracoscopic pericardectomy, and thymoma resection. It has been shown that the use of vessel sealing devices can significantly decrease surgical time for certain applications such as canine ovariohysterectomy when compared to laparoscopic hemoclip application and extracorporeal suture placement.2 A variety of units are currently available. Two bipolar electrocautery devices are the Ligasure™ (Valleylab, Tyco Healthcare Group) and the Enseal™ (SurgRX Inc.). Both devices have tips that are indicated to seal arteries and veins up to 7 mm in diameter. The Ligasure has the advantage of sensing the tissue impedance within the jaws of the tip that then adjusts the energy output from the generator accordingly to ensure a safe and effective seal. The Harmonic Scalpel® (Ethicon Endo-surgery) is a device that uses ultrasonic energy to cut and coagulate tissue. The Harmonic Ace® tip is indicated to seal vessels up to 5 mm in diameter. Several reports have compared these devices with respect to the degree of lateral thermal spread, bursting pressures and sealing time although the results of these studies are often conflicting.3,4 Overall, however, all produce supra-physiological bursting pressures of at least three times systolic blood pressure.3 For the Ligasure lateral thermal spread ranged from 1.5-3.2 mm in one study with a greater degree of thermal spread seen as vessel size increased.5 Although generally very safe, care must nevertheless be taken when these devices are used adjacent to neurovascular or other vital structures. Other vessel-sealing technologies are emerging onto the market constantly.

References 1. Dubiel B, Shires PK, Korvick et al. Electromagnetic energy sources in surgery. Vet Surg 2010;39:909-924 2. Mayhew PD, Brown DC. Comparison of three techniques for ovarian pedicle hemostasis during laparoscopic-assisted ovariohysterectomy. Vet Surg 2007;36:541-547 3. Person B, Vivas DA, Ruiz D, Talcott M, Coad JE, Wexner SD. Comparison of four energy-based vascular sealing and cutting instruments: a porcine model. Surg Endosc 2008 22:534-538 4. Lambertson GR, Hsi RS, Jin DH, Lindler TU, Jellison FC, Baldwin DD. Prospective comparison for four laparoscopic vessel ligation devices. J Endourol 2008 22:2307-2312 5. Carbonell AM, Joels CS, Krecher KW, Matthews BD, Sing RF, Heniford BT. A comparison of laparoscopic bipolar vessel sealing devices in the hemostasis of small, medium and large-sized arteries. J Laparoendosc Adv Surg Tech 13:377-380; 2003

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Managing the Mystery Poisoning Patient Tina Wismer, DVM, DABT, DABVT ASPCA Animal Poison Control Center Urbana, IL

The practitioner is occasionally presented with a situation where it is suspected, either by the owner or the veterinarian, that an unidentified “poison” has intoxicated the patient. Although identification of the agent involved is often extremely helpful in determining proper treatment and prognosis, it is important to remember that the majority of these types of cases are managed without the offending agent ever being identified. Just because the identity of the toxicant remains a mystery does not mean that the veterinarian cannot deliver appropriate and effective treatment. Whether the toxic agent is known or not, it should always be remembered that the goal of the practitioner is to “treat the patient, not the poison.”

Assess the patient Upon initial examination, evaluation of the animal for immediate life-threatening problems such as seizures, apnea/dyspnea, hemorrhage, cardiac arrhythmias, and hyperthermia is essential. A brief history may be obtained from the client while the examination is taking place—more detailed history may be obtained after the animal is stabilized. Additional important information that should be obtained includes duration of signs, age and prior health status of the animal, and any initial signs that are no longer apparent.

Stabilize the patient Stabilization is a priority in animals presenting with severe clinical signs. Animals should be intubated and/or provided with supplemental oxygen as needed. If possible, obtain venous access and draw blood for laboratory profile and potential diagnostic testing (3 cc EDTA tube, 2 serum tubes are ideal), prior to administration of other medications. Standard anticonvulsants such as diazepam or barbiturates may be used to control seizures. Anticonvulsants, particularly benzodiazepines, should be administered slowly IV, as rapid administration may induce a dysphoric effect and temporarily exacerbate the situation. If the standard anticonvulsant therapy does not have any effect, consider inhalant anesthesia or a propofol CRI to allow for initial management of the patient. Life-threatening cardiac arrhythmias should be treated as needed (atropine, propranolol, or lidocaine prn); arrhythmias not deemed immediately life-threatening can be treated after a better history has been obtained. Intravenous fluids and blood or blood replacement agents should be administered as needed. Body temperature should be normalized as needed, however aggressive cooling measures should be undertaken with care. Any electrolyte or acid/base abnormalities should be corrected. Once the patient has been fully stabilized, a more comprehensive physical examination may be performed.

Obtain history Once the animal is stable, further questioning of the owner should be performed in an attempt to narrow down the possible causes for the animal’s signs. Questions to consider include how long since the last time the animal appeared normal to the owner, whether the onset of signs was gradual or sudden, the location of the animal in the last few hours prior to the development of clinical signs, and any history of administration of medications/herbal products/flea or tick control products to this animal or other animals in the household in the past 24 hours. The type of environment in which the animal lives (e.g. indoor only vs. indoor/outdoor vs. fenced yard vs. roaming) will help to determine the next lines of questions to ask. For indoor animals, information that may be useful includes the areas to which the animal has access, the types of medications/herbal products (human and veterinary, prescription, illicit and OTC) available, whether there have been recent visitors who may have dropped medication, the types of houseplants in the home, whether there are children or teenagers in the household, presence of rodenticides or insecticides, and whether other pets in the house appear normal. In cases where illicit drugs are involved, or where owners have inappropriately administered medications or other products to their pets, the veterinarian may notice some reluctance on the part of the owner to provide the requested information. Tactful questioning may aid in obtaining the desired information. In other cases, it may be helpful to mention that without knowledge of the agent involved, more intensive (and expensive) diagnostics and treatments may be necessary. For outdoor animals confined by fences or other means, identification of potentially toxic agents in outbuildings, garages or sheds to which the pet may have access is important. Other potential hazards found in yards include compost piles, plants, mushrooms, and yard treatments (especially some systemic insecticides and crabgrass killers). For free roaming animals, the challenge is much greater as the number of potentially toxic agents available is quite large. Determining whether the animal is in an urban, suburban, or rural environment and identifying the nature of the animal’s immediate surroundings (e.g. wooded areas vs. parks and lawns) may help in narrowing down the agents to which the roaming animal may have been exposed. The presence of livestock in the pet’s environment should stimulate questioning to determine the pet’s access to the barns or feed bins, whether medicated feeds, fly baits or feeds with 653

growth promotants in them are present, whether the livestock have recently been medicated or dewormed, and if any livestock have recently been euthanized and buried on the property.

Formulate rule-out list Armed with a thorough physical examination and as much history as is obtainable, the clinician should then formulate a list of differential diagnoses. It is important not to become so caught up in the certainty that the causative agent is a poison that one loses sight of potential etiologies of infectious, metabolic or other “non-toxic” origin. For instance, although a variety of toxicants may cause acute onset of seizures, other potential etiologies to consider include encephalitis, idiopathic epilepsy, hypoglycemia, head trauma, hypoxia, hepatic failure, acid/base abnormalities, etc.

Ancillary support General supportive care includes maintaining hydration, ensuring adequate urine output, monitoring of respiratory, cardiac and neurologic status, and managing clinical signs as they develop. Recumbent or comatose animals require careful monitoring and thermoregulation. Gastrointestinal protectants or anti-emetics may be required (e.g. NSAID overdosages). Management of secondary hepatic or renal injury is imperative.

Prevent toxicant absorption Decontamination should be instituted only after the animal has been fully stabilized. In clinically normal animals with suspected oral exposure to toxicants, emesis may be induced. Contraindications to emesis would include cases where animals have already vomited, are at risk of aspiration (e.g. CNS depression or other severe clinical signs), or have ingested corrosive agents, acids, alkalis, or hydrocarbons. In cases where animals are sedated or anesthetized (e.g. seizure control), gastric lavage may be considered; lavage is contraindicated if it is suspected that corrosive agents have been ingested. The gastric contents from spontaneous or induced emesis or gastric lavage should be kept in case analytical testing is desired in the future. Contents should be placed in a clean glass jar with a tight lid and kept refrigerated or frozen. If there could be possible legal action, seal with tape and initial/date sample. It is important to maintain records of chain of custody of samples (vomitus, carcass, etc.). Administration of activated charcoal is recommended for most cases of ingested poisons, although it is contraindicated in cases where oral exposure to potentially corrosive agents is suspected. For dermal exposures, animals should be bathed in liquid dish soap such as Dawn or Palmolive and rinsed copiously with warm water. Use of aprons, gloves and goggles by the veterinary staff during dermal decontamination will minimize human exposure to the toxicant.

"The antidote" If, after stabilizing the animal and obtaining an adequate history, the toxic agent has been identified, specific antagonists may be indicated (e.g. Vitamin K for rodenticides). It is important to remember that the vast majority of toxic agents have no specific antidote, so the treatment will be, by necessity, symptomatic and supportive. Even in cases where antidotes do exist for the specific toxicant, there are often barriers to their use in veterinary medicine, including high cost and lack of availability (e.g. pamidronate for cholecalciferol or calcipotriene toxicosis).

Analytic testing Unfortunately, there is no one test that will “screen” for all known toxicants, and multiple tests for specific agents can become costly. In general, one needs to have an idea of the general type of agent that may be involved before analytical testing is attempted. For suspected human medication ingestion, human hospitals may be willing to run tests for illicit drugs, antidepressants, cardiac drugs, acetaminophen, etc. on a STAT basis. Alternatively, there are now available in many human pharmacies, OTC home drug testing kits that might be considered; these bench-top tests, though technically not validated for non-humans, are quick, easy and cost-effective in cases of suspected exposure to certain human medications. For suspected rodenticide, insecticide, or heavy metal exposure, most veterinary diagnostic laboratories offer basic screens. Some diagnostic laboratories offer specialty screenings, such as “convulsant” screens that might detect agents such as bromethalin, tremorgenic mycotoxins, strychnine, etc. In many cases, the results from these tests may not be obtained for days, at which point the patient may be either recovered or dead. Therefore, the veterinarian should still be prepared to manage the case using appropriate symptomatic and supportive care.

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Mood-Altering Drugs and Serotonin Syndrome Tina Wismer, DVM, DABT, DABVT ASPCA Animal Poison Control Center Urbana, IL

With the large number of people and animals that are on antidepressant medications it is not surprising that the number of accidental ingestions of these drugs has also increased. Advances in medicine have lead to the development of medications capable of targeting specific biochemical mechanisms thought to be responsible for a variety of mental health disturbances. The increase in the number of drugs that affect serotonin metabolism reflects the discovery of the role of serotonin in maintenance of mental health. Serotonin has been determined to be involved with regulation of personality, sleep, temperature, sexual function, aggression, motor control, pain perception and cardiorespiratory function. Serotonin acts peripherally to stimulate smooth muscle and centrally as an inhibitor of excitatory neurotransmission. When overdosage of serotonergic drugs occurs, the result may be serotonin syndrome, a potentially life threatening multi-systemic disorder caused by over stimulation of serotonin receptors within the CNS and other systems.

Formation of serotonin Serotonin is formed from tryptophan, an essential amino acid. Tryptophan, in competition with other amino acids, crosses the blood- brain barrier via a non-selective transporter mechanism. Within the CNS, tryptophan readily enters neurons and is subsequently converted to 5-hydroxytryptophan (HTP) by the enzyme tryptophan hydroxylase. This conversion is saturable and is the rate-limiting step in the formation of serotonin. The 5-hydroxytryptophan is then rapidly converted to serotonin (hydroxytryptamine). Serotonin is packaged in vesicles and released at the synapse during depolarization of the presynaptic neuron. Serotonin subsequently binds to receptors on the postsynaptic neuron, stimulating its depolarization or binds to receptors on the presynaptic neuron where it inhibits further release of serotonin. Its work accomplished, serotonin is pumped back into the presynaptic neuron, where it is either recycled into vesicles for future release or broken down to metabolites (primarily hydroxyindoleacetic acid) through the action of the enzyme monoamine oxidase.

Mechanism of action With evidence that increasing brain serotonin levels may have antidepressant and anxiolytic effects in humans (and possibly other animals), many serotonergic drugs have been investigated. The drugs can be classified by how they effect serotonin (see Figure 1):  Drugs that enhance serotonin synthesis (L-tryptophan, L-5-hydroxytryptophan)  Drugs that increase presynaptic serotonin release (amphetamines, amphetamine derivatives, monoamine oxidase inhibitors [MAOIs], cocaine)  Drugs that inhibit serotonin uptake into the presynaptic neuron (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], amphetamines, cocaine, dextromethorphan, meperidine)  Drugs that inhibit serotonin metabolism (MAOIs)  Drugs that act as serotonin agonists (buspirone, sumatriptin, LSD). When these drugs do their jobs too well, or when overdoses occur, serotonin syndrome can result. The syndrome most commonly occurs in human when two or more serotonergic agents with different mechanisms of action are administered either concurrently or in close succession, leading to excessive levels of serotonin in the CNS. (see Table 1) Serotonin syndrome most commonly occurs in dogs secondary to inappropriate ingestion of the owner’s medications.

Clinical signs Serotonin syndrome was originally classified in humans and defined as a constellation of symptoms that included at least three of the following: myoclonus, mental aberration (dementia, disorientation, etc.), agitation, hyperreflexia, tremors, diarrhea, ataxia and hyperthermia. This “classic” definition of serotonin syndrome has recently become controversial although a majority of cases of serotonin syndrome in humans and animals will fulfill these criteria. In addition to the CNS and GI tract (where serotonin is a modulator of gastrointestinal smooth muscle contractility), respiratory and cardiovascular function may be altered in serotonin syndrome due to the importance of serotonin in maintaining vascular tone, stimulating bronchial smooth muscle, and stimulating cardiac stroke rate and volume. In general, these effects are not as clinically relevant as the GI and CNS signs. Alteration in platelet function or coagulation, both areas in which serotonin plays important role, has not been described in cases of serotonin syndrome in humans or animals. In dogs the most common clinical signs include (in descending order): vomiting, diarrhea, seizures, hyperthermia, hyperesthesia, depression, mydriasis, vocalization, death, blindness, hypersalivation, dyspnea, ataxia/paresis, disorientation, hyperreflexia, and coma. Signs are similar, but vary in severity, whether 5-HTP or other serotonergic drugs such as SSRIs or MAOIs are ingested.

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History of serotonin syndrome The earliest account of serotonin syndrome in people was published in 1955, but the term serotonin syndrome was not used until 1982. Diagnosis There are no diagnostic tests to confirm serotonin syndrome, and the diagnosis will need to be based on history of ingestion of serotonergic drugs and presence of compatible clinical signs. Decontamination Emesis should only be attempted in asymptomatic animals. Gastric lavage may be used in cases of large ingestions. Most of the medications that can cause serotonin syndrome bind well to activated charcoal (lithium is the exception) and many times this is the only decontamination procedure needed. Repeated doses of activated charcoal may need to be used with ingestions of TCAs or other medications that undergo enterohepatic recirculation. A cathartic should be used along with the first dose of activated charcoal. Do not use magnesium salts as a cathartic in TCA ingestions as the decreased peristalsis caused by TCAs can result in increased magnesium absorption. An enema may also be given if sustained release products are consumed. Treatment Treatment of serotonin syndrome is largely symptomatic and supportive. Inducing vomiting is not recommended if clinical signs are present because of the increased risk of aspiration. Seizures and agitation generally respond to diazepam or phenothiazines (the drug of choice in humans), and barbiturates can be used in refractory cases. Because hyperthermia is a significant concern, cooling measures should be instituted. Diuresis does not enhance excretion, but intravenous fluids should be administered to support the cardiovascular system, aid in thermoregulation, and maintain renal blood flow. The use of cyproheptadine, a nonselective serotonin antagonist, has shown to be a helpful adjunct in managing serotonin syndrome in animals. Cyproheptadine may be administered at a dose of 1.1 mg/kg PO (dogs) or 2-4 mg PO (cats). In cases where the oral route is not feasible (e.g. severe vomiting), cyproheptadine may be crushed and mixed with saline to be instilled rectally. Doses of cyproheptadine may be repeated every 4-6 hours as needed until signs have resolved. Propranolol also has some serotonin blocking effect, and may be of benefit if animals are tachycardic. Administration of activated charcoal is important, but only once the animal has been reasonably stabilized. Metabolic acidosis may occur and can be corrected with sodium bicarbonate as indicated by blood gas analysis. Symptomatic care to control vomiting, abdominal pain, or other signs can be instituted as needed. Prognosis In most cases, signs will subside over 12 to 24 hours and full recovery is expected within 48 hours in uncomplicated cases. The outcome depends on dose, treatment, and exposure to other highly protein bound medications. The prognosis also depends on the overall health of the dog, especially if there is a history of liver and/or renal disease. Liver disease can inhibit metabolism of these drugs and renal disease can delay excretion. Potential sequelae include rhabdomyolysis, disseminated intravascular coagulation, and renal failure secondary to myoglobinuria. Prognosis is generally good with rapid and aggressive therapy.

Table 1. Serotonergic potential of various drugs High Medium Low Amitriptyline (Elavil®) Buspirone (BuSpar®) Amantadine Clomipramine (Clomicalm®, Anafranil®) Cocaine Bromocriptine (Parlodel®) Dexfenfluramine (Redux®) Desipramine (Norpramin®) Bupropion (Wellbutrin®, Zyban®) Dextromethorphan Doxepin (Adapin®, Sinequan®) Fenfluramine (Ponderal®) L-Dopa Carbamazepine (Tegretol®) Codeine Fluoxetine (Prozac®) LSD (lysergic acid diethylamide) Fluvoxamine (Luvox®) Nortriptyline (Pamelor®) Melatonin Mirtazapine (Remeron®) Imipramine Trazodone (Desyrel®) Isocarboxazid (Marplan®) Nefazodone (Serzone®) Pentazocine (Talwin®) Lithium MDMA (methylenedioxymethamphetamine) Pergolide (Permax®) Tramadol (Ultram®) Meperidine Moclobemide (Manerix®) Paroxetine (Paxil®) Phenelzine (Nardil®) Selegiline (Anipryl®, Eldepryl®) Sertraline (Zoloft®) Tranylcypromine (Parnate®) Venlafaxine (Effexor®)

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Hot Topics in Clinical Toxicology Tina Wismer, DVM, DABT, DABVT ASPCA Animal Poison Control Center Urbana, IL

The good Silica gel packs Desiccant packs are included as moisture absorbents. Most ingestions will not cause clinical signs, although a mild gastrointestinal upset may occur. Ant and roach baits Ant and roach baits are common objects found in households. The insecticides used most commonly in these baits are fipronil, avermectin, sulfluramid, boric acid, indoxacarb and hydramethylnon, all of which are of low mammalian toxicity and present in very low concentrations within the baits. The baits also contain inert ingredients such as peanut butter, breadcrumbs, fats and sugar to attract the insects; these agents are also sometimes attractive to pets. Birth control pills Birth control pills generally contain estrogen and progestins. Estrogen doses of less than 1 mg/kg are not of concern. At higher doses, bone marrow suppression may be seen. Glow-in-the-dark sticks and jewelry The primary luminescent agent in these types of products is dibutyl phthalate (n-butyl phthalate), an oily liquid that is also used as a plasticizer and insect repellent. Dibutyl phthalate is of low toxicity (LD50 >8000 mg/kg in rats) but has an extremely unpleasant taste. Taste reactions are commonly seen. Toilet water (tank drop-ins) Tank "drop in" products typically contain anionic/nonionic detergents, cationic detergents, bleach, and/or acids. However, when a tank "drop in" cleaning product is used in a toilet, dilution occurs and the cleaning agent is just a gastric irritant. Cyanoacrylate glues Cyanoacrylates (Super Glue®) solidify when they contact saliva, so minimal absorption occurs. Fertilizers Fertilizers are made up of nitrogen, phosphorus, and potassium (NPK) in various ratios. Fertilizers generally have a wide margin of safety and only mild GI signs are expected after ingestion. Additives to fertilizers may include herbicides, insecticides, fungicides, iron, copper, and zinc. These additions increase the likelihood of GI and systemic signs.

The bad Anticoagulants Anticoagulants in use as rodenticides today are almost all second-generation derivatives. They inhibit the activity of vitamin K epoxide reductase, which converts vitamin K epoxide to the active reduced form. This reduced vitamin K is crucial to activation of clotting factors II, VII, IX, and X. Any exposure > 0.02 mg/kg of a second generation anticoagulant requires treatment and evaluation. Emesis can be induced if ingestion has occurred within the last 4 hours. If little or no bait is recovered, administration of activated charcoal is next. Another option is to institute Vitamin K1 therapy (2.5-5 mg/kg/day) or monitor PT tests. Because the body has several day’s worth of active Vitamin K stored in the liver (the site of the re-activation activity), there is a delayed onset of effect on blood clotting after ingestion of an anticoagulant. Factor VII has the shortest half-life, so we can get the earliest valid estimate of effect by checking the prothrombin time (PT). The PT is expected to elevate within 24-48 hours post ingestion. Early signs of anticoagulant toxicosis are vague, and depend on the site of a bleed. Lethargy, non-productive cough, intermittent lameness, mild anemia, or even sudden collapse can be seen. Petechiae and echymoses are more often seen later in the course of illness, after the platelet numbers have been depleted in smaller bleeds. Diagnosis is based on signs, history of possible exposure, and coagulation studies. If the animal is actively bleeding, start vitamin K1 and give clotting factors via a whole blood transfusion, fresh frozen plasma, or fresh plasma. Minimize physical activity throughout therapy. Bromethalin Bromethalin is a neurotoxin that uncouples oxidative phosphorylation in CNS mitochondria. This results in lack of adequate ATP concentration and insufficient energy for maintaining Na+-K+ ion channel pumps. Loss of pump activity results in cerebral and spinal cord edema and a demyelination injury to long nerves. Bromethalin is rapidly absorbed from GI tract. Cats are far more sensitive to this agent than are dogs. Dogs seem to have both a low-dose and a high-dose syndrome. With lower doses signs may not appear for 72-96 hours, and include hind limb ataxia and paresis, decreased proprioception, loss of deep pain response, vocalizations, patella hyper-reflexia, CNS depression progressing to coma,

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vomiting, and fine muscle tremors. At or above the mean lethal dose, signs can begin within 12-24 hours and include severe tremors, hyperthermia, extreme hyperexcitability, running fits, hyperesthesia and seizures. Treatment of clinical signs is directed to controlling cerebral edema, and is mostly frustrating and non-productive. Mannitol, corticosteroids and diazepam may be used. Animals with sub-lethal doses will require good nursing care. Cholecalciferol

Cholecalciferol is a Vitamin D3 analog. It alters calcium metabolism in the body, increasing intestinal absorption and renal tubular reabsorption of calcium and stimulating bone resorption. Clinical signs of intoxication usually develop within 12-36 hours. Early signs include lethargy, weakness, anorexia, polydipsia, polyuria, and vomiting, often with blood. Biochemical alterations include hyperphosphatemia within 12 hours and hypercalcemia within 24 hours of exposure and azotemia (both renal and pre-renal). The elevated calcium levels result in calcification of many tissues, notable renal tubules and walls of blood vessels. The elevated calcium also has a direct effect on kidney function, sometimes causing acute renal failure even without mineralizations. Diagnosis of toxicosis is based on history of exposure, clinical signs, serum chemistries and urinalysis. Run baseline chemistries as soon as possible after a known exposure. Pursue GI decontamination if within several hours of ingestion, or if there is evidence of ingestion (chewed box) at unknown time but a still asymptomatic animal. Multiple doses of activated charcoal and cholestyramine can help decrease absorption. Treatment is aimed at lowering the serum calcium and phosphorus levels, preventing a rise in these values if still normal, and stopping further calcium mobilization from the bones. IV normal saline at twice maintenance, prednisone and furosemide all enhance calciuria. Monitor serum calcium, phosphorus, BUN and creatinine daily to judge effectiveness of therapy. If calcium levels are rising despite calciuresis, best choice is pamidronate (Aredia™). Unlike salmon calcitonin, it needs to be given only once, with a repeat dose possibly at about 5-7 days. It acts at the level of the osteoclast and is deposited in the bone itself. Once the pamidronate has been administered, it is important to taper the initial treatments (prednisone, furosemide) and decrease the rate of fluid administration. Continue to monitor calcium, phosphorus, and kidney values during this time. End of therapy will be marked by a return to normal of kidney values and the decrease of calcium x phosphorus levels (in mg/dl). Zinc phosphide Zinc phosphide is an old rodenticide posing as a new one. The phosphide salts are unstable in an acid environment. At gastric pH they degrade rapidly to form phosphine gas. Phosphine gas, when inhaled, results in acute non-cardiogenic pulmonary edema. When absorbed systemically, it is thought to block cytochrome C oxidase, leading to formation of highly reactive oxygen compounds. It is these reactive compounds which cause most of the tissue injury, most severe damage is in tissues with the highest oxygen demand – brain, lungs, liver and kidney. Lethal doses for cattle, sheep, pigs, goats, dogs, and cats range between 20-50 mg/kg. For a 55 pound (25 kg) dog, that would be between 10 grams (0.35 ounce) and 25 grams (just under an ounce) of 5% bait. Severely poisoned animals may die in 3-5 hours. Those who survive longer than 48 hours have a pretty good chance. Initial signs may vary by species, as well as by the dose. Onset of signs is normally between 15 minutes to 4 hours post ingestion. Vomiting, often with blood, is common. Dogs may show lateral recumbency with whole body tremors and salivation. Other signs may include anorexia and lethargy. Rapid deep breathing may signal the onset of the pulmonary changes. Abdominal pain, ataxia, and weakness leading to recumbency may follow. Hyperesthesia and seizures may develop that resemble the signs of strychnine toxocosis. Metabolic acidemia ensues. Other biochemical changes may include depressed serum calcium and magnesium. If there is survival beyond 48 hours an elevated blood urea is common. Hepatic and renal damage often may be detected 5-14 days later. Initial decontamination is tempered by the wish to keep the stomach pH as high as possible to prevent the formation of phosphine gas. If there has been no spontaneous vomiting, it may be better to induce emesis with apomorphine rather than hydrogen peroxide. Giving food, commonly done in order to improve gastric emptying and the response to peroxide, will trigger release of gastric acid and increase the rate of production of phosphine. If you are going to perform gastric lavage, add an alkalizing component like a magnesium and aluminum hydroxide gel to your lavage liquid. Also consider mixing into your activated charcoal preparation. Supportive care includes IV fluids to maintain blood pressure renal perfusion, and gastroprotectants. Seizures may respond to diazepam, or may require barbiturates or full anesthesia. Since the most severe injury is probably due to action of the oxygen radicals, use of an antioxidant may be useful – consider vitamin C or n-acetylcysteine. Caution: Phosphine gas released from vomitus or stomach washings can cause significant illness in veterinary personnel assisting animal. Phosphine has been describes as having a spoiled fish or garlic odor. It is detectable at 1-3 ppm in air; maximum allowed in air in occupational situations is 0.3 ppm, so if you can smell it, you are being exposed to a concentration that can be harmful. Corrosives: Acids, alkalis, cationic detergents Products containing acids, alkalis or cationic detergents can cause local corrosive damage. Clinical signs occur almost immediately upon exposure with acids, but can be delayed up to 12 hours with alkalis or cationics. Oral exposure results in pain, vocalization, dysphagia, vomiting (+/- blood), and irritation or ulceration of oral and/or esophageal mucosa. Significant hyperthermia (>104 F) may accompany oral inflammation.

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Batteries When batteries are chewed and the alkaline gel is released, liquifactive necrosis results (see Alkali section). Foreign body obstruction may occur when casings are swallowed and disc batteries may be inhaled, resulting in acute dyspnea and cyanosis. Pennies Ingestion of pennies can result is zinc toxicosis. In the stomach, gastric acids leach the zinc from its source, and the ionized zinc is readily absorbed into the circulation, where it causes intravascular hemolysis. Polyurethane adhesives Isocyanate glues (Gorilla Glue®, Elmer’s ProBond Polyurethane Adhesive®) are expanding wood glues that have been associated with gastric foreign bodies.

The tasty Bread dough (yeast) Rising yeast bread dough produces carbon dioxide and ethanol. This can result in bloated drunk dogs. Chocolate The active (toxic) agents in chocolate are methylxanthines, specifically theobromine and caffeine. Methylxanthines stimulate the CNS, act on the kidney to stimulate diuresis, and increase the contractility of cardiac and skeletal muscle. The relative amounts of theobromine and caffeine will vary with the form of the chocolate (see Table 1). Macadamia nuts Macadamia nut ingestion in dogs can cause weakness, depression, vomiting, ataxia, tremors, transient paresis, and hyperthermia. Most animals return to normal within 48 hours. Avocados Species sensitivity among animals varies. In dogs and cats, avocados are likely of low toxicity. In other species, sterile mastitis and myocardial necrosis can occur. Moldy food (tremorgenic mycotoxins) Tremorgenic mycotoxins produced by molds on foods are a relatively common, and possibly under-diagnosed, cause of tremors and seizures in pet animals. These molds grow on practically any food, including dairy products, grains, nuts, and legumes; compost piles may also provide a source of tremorgens. Clinical signs include fine muscle tremors that may rapidly progress to more severe tremors and seizures. Table 1. Methylxanthine levels of various chocolates Milligrams per ounce Compound Theobromine Caffeine White Chocolate 0.25 0.85

Milk Chocolate 58 6

Semi-sweet Chocolate chips 138 22

Baker’s Chocolate (unsweetened) 393 47

Dry cocoa powder 737 70

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New Antidotal Therapies Tina Wismer, DVM, DABT, DABVT ASPCA Animal Poison Control Center Urbana, IL

Antidotes can be divided into three broad categories: chemical antidotes, pharmacologic antidotes, and functional antidotes. Chemical antidotes act directly on the toxicant to make it less toxic and/or more readily excreted. Pharmacologic antidotes antagonize toxic agents at their receptor sites or through other macromolecules. Functional antidotes are agents that act on the symptoms of poisoning. In many cases, these antidotes have no real effect on the toxicant itself, but they lessen the severity of the clinical picture of the intoxicated patient.

Chemical antidotes: chelators Deferoxamine Deferoxamine (Desferal®, Ciba) is a chelating agent approved for use in humans for the treatment of acute iron poisoning, chronic iron overload and treatment of chronic aluminum overload in patients on chronic dialysis. It has been used off label to treat iron toxicosis in animals. Deferoxamine forms a chelate complex with free iron, which is then excreted in the urine and bile. Deferoxamine is most effective within the first 24 hours, before the iron has been distributed to the tissues. The extrapolated animal dose for iron toxicosis is 40 mg/kg, IM, every 4-8 hours. The IM route is preferred, as too rapid IV administration can cause hypotension and pulmonary edema. The efficacy of deferoxamine can be increased by giving ascorbic acid after the gut has been cleared of iron. The deferoxamine-iron complex gives a salmon pink color to the urine (“vin rose”). Continue to chelate until urine clears or until serum iron levels return to normal. DMSA (2,3-dimercaptosucinic acid, succimer) Succimer (Chemet®, McNeil Consumer Products) is approved for the treatment of childhood lead poisoning. It has also been used to treat arsenic and mercury poisoning and does not bind iron, calcium or magnesium. Succimer is available as 100 milligram capsules. It is a structural analog to BAL (British Anti-Lewisite, dimercaprol) but has less potential to cause nephrotoxicity. Succimer is preferred over Ca-EDTA and penicillamine, as succimer can be given while lead is still in the GI tract (the other 2 increase lead absorption), it comes in an oral form, it has a lower incidence of causing GI upset and it is also less likely than the others to induce Zn deficiency. Succimer, however, is more expensive than the other options (capsules are approximately $4 apiece). Although not approved for animal use, there are published doses for treating lead toxicosis. The dose for dogs and cats is 10 mg/kg PO TID for 10 days (administer on empty stomach; per rectum if animal is vomiting). Dosing for caged birds is 25-35 mg/kg PO BID 5 days a week for 3-5 weeks. Higher doses (80 mg/kg) have caused death in cockatiels. It is not uncommon for there to be a post-chelation rebound (or elevation) of blood lead levels. Most of the time, this is due to redistribution of the lead from bone and tissue stores in animals chronically exposed to lead. If lead levels are still increased and the animal is still symptomatic, a repeated round of therapy can be pursued. If the animal is asymptomatic, there is no need to retreat.

Chemical antidotes: immunotoxicotherapy Crotalidae polyvalent immune FAB (Ovine) Crotalidae polyvalent immune Fab (ovine) (CroFab®, Fougera) is approved for the management of patients with North American crotalid snake envenomation. The antivenin has been show to cross react with 10 North American crotalid species (see Table 1). In a recent study, CroFab® was given to 115 dogs presented to several veterinary emergency hospitals in the western US. The CroFab® gave “excellent results” although some dogs did require more than one vial (average dosing was 1.25 vials). This study also reported significantly less reactions to the CroFab® product compared to Ft. Dodge/Wyeth equine antibody antivenin (advantage of Fab over whole IgG). Early use (within 6 hours of snakebite) is recommended to prevent clinical deterioration and the occurrence of systemic coagulation abnormalities. Crotalid Fab is diluted in 250 mL of saline and infused over 60 minutes, with monitoring for development of an allergic reaction during the first 10 minutes. Recurrence of local symptoms of crotalinae envenomation following CroFab® treatment has been reported in people, probably due to the short half-life of the antivenin. Cost is approximately $1400/2 vials. Digoxin immune Fab Digoxin immune Fab (Digibind®, Burroughs Wellcome) is produced from specific digoxin antibodies from sheep and will bind directly to digoxin or digitoxin and inactivate it. Antidigitoxin Fab fragments have an affinity for digoxin that is much higher than the affinity of digoxin for its sodium-potassium ATPase target. Digibind® has sufficient cross reactivity and can also be effective against bufotoxins (Bufo toads) and plants containing cardiac glycosides (see Table 2). Treatment with Fab fragments should be considered in those patients who fail to respond to conventional therapy. Signs of severe toxicity might include severe ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation), progressive bradyarrhythmias

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(severe sinus bradycardia), or second or third degree heart block not responsive to atropine. The dosage varies based on the amount of digoxin to be neutralized. The best situation is to have a human hospital run digoxin levels and then dosing is based on those results. The dose of Digibind® is calculated: Digibind® dose (number vials) = [Serum Digoxin Concentration (ng/mL) x Patient's weight (kg)] / 100. The next best method is to estimate the body load of digoxin ingested (almost impossible with toads or plants). Body load is estimated as dose ingested x 0.8. The formula is then: Digibind® dose (number vials) = [Body load (mg) / 0.5 (mg/vial)]. If either of these methods are not feasible then it is suggested that 1-2 vials be administered and the effects observed. Each vial of Digibind® contains 38 mg which will bind approximately 0.6 mg of digoxin or digitoxin. Reconstitute each vial with 4 mL of sterile water or isotonic saline. Administer slow IV over 30 minutes, infused through a 0.22 micron filter (if possible). Digibind® can be a life saving treatment however, it is expensive ($2200/5 vials).

Chemical antidotes: enzyme inhibitors Fomepizole (4-MP, 4-methylpyrazole) Fomepizole (Antizol-Vet®) is a competitive inhibitor of alcohol dehydrogenase. It was approved for use in dogs to treat ethylene glycol (EG) toxicosis in 1997. Each vial contains 1.5 g of fomepizole and the reconstituted solution is 50 mg/ml. Shelf life is 72 hours once reconstituted. The advantages of fomepizole are that is does not induce hyperosmolality, CNS depression, and diuresis (vs. ethanol). Dogs may be treated as late as 8 hrs post ingestion and still have a favorable prognosis. Fomepizole may still be effective as late as 36 hrs post-ingestion of EG. The recommended dosing regime for dogs is an initial IV injection of 20 mg/kg (give over 15-30 minutes), followed by 15 mg/kg slow IV at 12 hours and again at 24 hours. A last dose of 5 mg/kg IV is given at 36 hours after the first injection. Since fomepizole slows down the metabolization of EG, serum levels may still be detectable at 72 hours after ingestion. If the EG test is still positive after the last dose continue treatment at 5 mg/kg IV every 12 hours until test is negative. Fomepizole is not labeled for cats but preliminary clinical trial results suggest that high doses of fomepizole in the cat (125mg/kg slow IV infusion loading, then 31.25 mg/kg at 12, 24, 36 hrs post EG ingestion) are safe and effective when therapy is initiated within 3 hours following EG ingestion. [Note: at 3 hrs post lethal dose EG administration, 100% recovery with fomepizole, 25% recovery with ethanol. At 4 hrs post EG, 100% mortality with fomepizole and ethanol was noted in these studies]. Other than calcium oxalate crystals in the urine, no biochemical evidence of renal impairment was noted out to 2 weeks post EG exposure and fomepizole.

Pharmacologic antidotes: receptor antagonists Flumazenil Flumazenil (Romazicon®, Roche) is an imidazobenzodiazepine derivative, which antagonizes the CNS actions of benzodiazepines. Flumazenil binds to and rapidly displaces benzodiazepines from the benzodiazepine receptor, thereby reversing their sedative and anxiolytic effects within 1-2 minutes. It is indicated in people for diagnosis of benzodiazepine overdose and reversal of benzodiazepine sedation and respiratory depression. Use in animals is usually limited to those at risk of respiratory depression. The dose is 0.01 mg/kg, IV, for both dogs and cats and can be repeated if severe depression returns. The half-life for flumazenil is about 1 hour, so repeated injections may be needed. Flumazenil may also be given intratracheally in an emergency situation. Flumazenil is contraindicated in patients suspected of tricyclic antidepressant overdoses as it can cause seizures. Atipamezole Atipamezole (Antisedan®, Pfizer) is an α2-adrenergic antagonist labeled for use as a reversal agent for medetomidine, but it can also be used to treat several toxicoses. Atipamezole can be used to reverse other α2-adrenergic agonists (amitraz, xylazine, bromonidine, clonidine and tizanidine). Atipamezole quickly reverses the hypotension and bradycardia seen in these toxicoses. After IM administration in the dog, peak plasma levels occur in about 10 minutes. Atipamezole has an average plasma elimination half life of about 2-3 hours (vs. yohimbine half life of 1.5-2 hr in dogs) and may need to be repeated.

Functional antidotes Bisphosphonates Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Pamidronate (Aredia®, Novartis) inhibits osteoclastic bone resorption and was developed to treat hypercalcemia of malignancy in people. Pamidronate can be used in dogs for treating hypercalcemia secondary to cholecalciferol toxicosis. The recommended dose of pamidronate for dogs is 1.3 - 2.0 mg/kg as a slow IV infusion in 0.9% sodium chloride over 2-4 hours. The advantage of pamidronate over salmon calcitonin is that it has long lasting effects (may need to repeat once in 5-7 days). Do not use in combination with calcitonin. The downside of pamidronate is that it is expensive ($275-400/vial), however, when compared to length of hospitalization and the labor involved in the repeated doses of calcitonin, the cost is comparable.

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New antidotal uses for other drugs (teaching old dogs new tricks) Intralipids Intralipids are lipid emulsions. Lipid emulsions are commonly used as a fat component for parenteral nutrition. While more studies are needed, lipid therapy is very exciting new treatment for lipid soluble toxicoses. Lipid use is based on human research investigating bupivacaine overdoses. The possible mechanism for lipid rescue is that the lipids bind to the fat soluble toxin (“lipid sink”) and bound toxin is inactive. Liposyn, or any other 20% lipid solution, can be given through a peripheral catheter and is relatively inexpensive. A bolus of 1.5 ml/kg is given (over 1 minute if cardiac arrest, slower otherwise), followed by 0.25 ml/kg/min for 30-60 minutes. This is repeated in four hours if the serum is clear. Lipid therapy can hasten recovery time in some cases. There are possible complications to lipid therapy: significant lipemia, pancreatitis, transiently increased liver enzymes, volume overload and lipids can also remove antidotes and other therapies. Cholestyramine Cholestyramine is an anion exchange resin available by prescription only. It is used to lower cholesterol in patients who have not responded to normal therapies. Cholestyramine has been used in human medicine to aid in the treatment of toxicoses (amiodarone, digitoxin, chlordane, methotrexate, piroxicam, vitamin D, warfarin, blue-green algae, indomethacin). It binds with bile acids in the intestine, preventing their reabsorption. This stops enterohepatic recirculation. Cholestyramine is not absorbed out of the digestive tract, so it has no systemic effects, but constipation and mild liver enzyme elevation may be seen. The dose is 0.3 – 1 g/kg TID for several days (depends on toxin ingested). For our patients, the powder should be given or mixed with canned food. Cholestyramine is cost effective with a price around $50-80 for 240g. Cyproheptadine Cyproheptadine(Periactin®, Merck) is an antihistamine (H1 blocker) that also has serotonin antagonistic activity. Cyproheptadine has been used in veterinary medicine for its antihistaminic and appetite-stimulant effects (cats) and is now being used to help treat serotonin syndrome. Serotonin syndrome is a condition caused by serotonin excess within the CNS and is characterized in dogs by tremors, seizures, hyperthermia, ataxia, vomiting, diarrhea, abdominal pain, excitation or depression, and hyperesthesia. Serotonin syndrome has been associated with the use of drugs that increase brain serotonin levels (e.g. selective serotonin reuptake inhibitors, amphetamines) in humans and after accidental ingestion of 5-hydroxytryptophan (serotonin precursor) in dogs. The recommended dose for dogs is 1.1 mg/kg PO or per rectum every 1-4 hours until signs subside. N-acetylcysteine N-acetylcysteine (NAC, mucomyst) is the N-acetyl derivative of L-cysteine, a naturally occurring amino acid. Although originally used as a mucolytic agent in people, NAC has become an important part of managing acetaminophen overdoses in people and animals. Because of NAC’s ability to minimize oxidative damage to the liver from acetaminophen, NAC had been investigated for its ability to prevent damage from other hepatotoxins. A recent study on Amanita phalloides (death cap mushroom) poisoned people showed that the use of a protocol similar to that used for acetaminophen toxicosis (high dose) was effective in preventing permanent hepatic injury in 10 of 11 people. Dantrolene Dantrolene (Dantrium®, Procter & Gamble Pharm.) has been mostly used in veterinary medicine for the prevention and treatment of malignant hyperthermia syndrome. Dantrolene may also be used to treat the malignant hyperthermia-like reaction seen in dogs after the ingestion of hops (Humulus lupulus). Hops are used in the brewing of beer. Recommended dose of dantrolene is 2-3 mg/kg, IV, or 3.5 mg/kg, PO, as soon as possible after ingestion.

Table 1. Cross reactivity of Crotalidae polyvalent immune Fab Scientific name Common name Agkistrodon picivorus Cottonmouth, water moccasin Agkistrodon contortrix contortrix Copperhead Crotalus adamanteus Eastern diamondback rattlesnake Crotalus atrox Western diamondback rattlesnake Crotalus horridus atricaudatus Canebrake rattlesnake Crotalus horridus horridus Timber rattlesnake Crotalus molossus molossus Northern blacktail rattlesnake Crotalus scutulatus Mojave rattlesnake Crotalus viridis helleri Southern Pacific rattlesnake Sistrurus malarius barbouri Pygmy rattlesnake

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Table 2. Cross-reactivity of antidigoxin Fab fragment with plant cardiac glycosides Scientific name Common name Acokanthera oblongifolia Adonis microcarpa Pheasant’s eye Asclepias physocarpa Balloon cotton bush Byrophyllum tubiflorum Mother of millions Calotropis procera King’s crown Carissa laxiflora Cerbera manghas Sea mango Convallaria majalis Lily of the valley Crytostegia grandioflora Rubber vine Helleboros sp Nerium oleander Oleander Thevetia neriifolia, T. peruviana Yellow oleander Urginea maritima Squill

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Toxicology of Herbal Medications Tina Wismer, DVM, DABT, DABVT ASPCA Animal Poison Control Center Urbana, IL

Herbal preparations are increasing dramatically in usage. A recent survey (2007) discovered that 38% of adults and 12% of children in the US have used at least one alternative therapy over the preceding 12 months. Many people not only use alternative therapies themselves, but also give various therapies to their pets, with or without advice from a veterinarian. The odds are that at least some clients in an average practice will have an interest in, or ask about the use of alternative medicine. The regulation of herbs and other dietary supplements differs from most pharmaceutical drugs. In 1994, the Dietary Supplement and Health Education Act (DSHEA) was created. This act includes vitamins, minerals, neutraceuticals, and herbs. Under the DSHEA, supplement manufacturers are not required to prove efficacy, safety, and there are no mandated quality controls. The FDA can intervene if enough adverse reactions to a specific product occur, but the burden of proof is on the FDA to prove a particular product is harmful. Manufacturers are allowed to state what effect a product is expected to produce (such as the antidepressant effects produced by St. John’s Wort) but the manufacturer can not claim a product specifically cures a stated effect. The label must include the statement that the claims have not been evaluated by the FDA.

Ma Huang, Sida cordifolia, and Citrus aurantium Ma Huang is produced from Ephedra sinica, as well as other Ephedra species and herbs such as Sida cordifolia. Other common names of ma huang include yellow horse and sea grape. S. cordifolia is often known as Indian common mallow. Bitter orange, Citrus aurantium, contains synephrine. Historically, ma huang has been used to treat asthma, colds and flu, fevers, congestion and coughs. Today, ma huang is frequently used as a weight-loss aid because of its stimulant properties and as a decongestant because it is vasoconstrictive. Ma Huang is also abused, like an illicit drug, because of its hallucinogenic and stimulant properties. When used as a weight-loss aid, frequently caffeine-containing plants are included in the formulation, which can increase toxicity. Some formulations will list the quantity of ephedrine per unit of drug. The active components of Ephedra sinica and Sida cordifolia are alkaloids, including ephedrine and pseudoephedrine. The FDA has banned Ephedra containing substances, but did not specifically list the active constituents. Products containing S. cordifolia and bitter orange cause the same clinical syndrome as those containing Ephdedra. Pharmacologically, ephedrine is a sympathomimetic alkaloid. The alkaloids stimulate alpha- and beta-adrenergic receptors, causing the release of endogenous catecholamines at synapses in the brain and heart. This stimulation results in peripheral vasoconstriction and cardiac stimulation. This results in increased blood pressure, tachycardia, ataxia, restlessness, tremors, and seizures.

Guarana Guarana is the common name of Paullinia cupana, a plant containing high levels of caffeine. Guarana may contain 3% to 5% caffeine by dry weight compared to coffee beans (1-2 % caffeine) and tea (1-4 % caffeine). Common names include Brazilian cocoa and Zoom. Theobromine and theophylline have also been found in the plant. Historically, guarana was used to provide energy during fasting, as an aphrodisiac, and to prevent malaria and dysentery. Guarana is frequently found in herbal weight loss aids (with or without ma huang) and in products promising increased energy. Because guarana contains methylxanthines, it produces a clinical syndrome similar to chocolate, coffee, or over the counter stimulant products which contain caffeine. Caffeine is a methylated xanthine. It increases cyclic AMP, releases catecholamines, and increases muscular contractility. The net effect is a positive inotropic and chronotropic effect on the heart, cerebral vasoconstriction, renal vasorelaxation, and smooth muscle relaxation in the gastrointestinal tract. Clinical signs include vomiting, restlessness and hyperactivity, polydipsia and polyuria. Tachycardia and other cardiac arrhythmias such as premature ventricular contractions (PVCs), are possible. Clinical signs progress to muscle tremors and seizures, and finally death.

Griffonia simplicifolia Griffonia simplicifolia seeds are used as a source of 5-hydroxytryptophan (5-HTP). This extract is generally used to treat depression, headaches, obesity and insomnia in humans. 5-HTP is reported to increase serotonin in the CNS. Label information may list 5-HTP, 5-hydroxytryptophan, or griffonia seed extract as an ingredient. Drug interactions with MAO inhibitors, antidepressants, and herbs such as St. John’s Wort can occur. 5-HTP is rapidly and well absorbed from the gastrointestinal tract. 5-HTP readily crossed the blood-brain barrier. Once target cells are reached, 5-HTP is converted to serotonin (5-hydroxytryptamine). Serotonin is important in the regulation of sleep, cognition, behavior, temperature regulation, and other functions. Clinical signs resemble serotonin syndrome in humans. Signs include seizures and tremors, depression, ataxia, and hyperesthesia. Gastrointestinal effects including vomiting, diarrhea, and drooling are common. Severe hyperthermia and blindness have been reported.

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Yohimbine Yohimbine is derived from the bark of Pausinystalia yohimbe. It has long been considered an aphrodisiac, and the bark was smoked as a hallucinogen. In traditional medicine, angina and hypertension were treated with yohimbine. Today, it is mostly used as a sexual stimulant, and is frequently marketed as herbal Viagra. Pharmacologically, yohimbine is classed as an alpha 2-adrenergic blocking agent. A first pass effect can be seen, and the drug is metabolized in the liver. Metabolites are eliminated in the urine. The T1/2 in dogs is 1.5-2 hours. In large doses, severe and life threatening clinical signs can be seen. Clinical effects are related to the alpha 2 blockade and subsequent CNS and cardiovascular stimulation. Clinical signs include hyperactivity, agitation, tremors, seizures, vomiting, diarrhea, abdominal pain, hypertension initially followed by a profound hypotension.

Alpha lipoic acid Alpha lipoic acid is a fat-soluble, sulfur-containing antioxidant. A variety of synonyms exist including lipoic acid, thioctic acid, acetate replacing factor, biletan, lipoicin, thioctaid and thioctan. Alpha lipoic acid is found in a variety of foods, especially yeast and liver. Spinach, broccoli, potatoes, skeletal muscle and organ meats like the heart and kidney are also good sources. In toxicology, alpha lipoic acid is useful in treating amanita mushroom poisoning. In veterinary medicine, it is used to treat diabetic polyneuropathy, cataracts, glaucoma, and ischemia-reperfusion injury. Alpha lipoic acid is synergistic with insulin, causing decreased blood sugar and increasing liver glycogenesis, and facilitates glucose uptake into cells. Clinical signs of toxicity include vomiting, ataxia, hypersalivation, tremors and hypoglycemia. Seizures can occur and symptomatic animals should be monitored for acute renal failure. Clinical signs can occur 30 minutes to several hours post-ingestion.

Chamomile Chamomile refers to both German chamomile (Matricaria recutita) and Roman chamomile (Chamaemelum nobile). Common names for German chamomile include wild chamomile and pin heads. Common names for Roman chamomile include garden chamomile, sweet chamomile, ground apple and whig plant. The plant is indigenous to Europe and northwest Asia and naturalized in America. German chamomile is an annual and Roman chamomile is a slow growing perennial. The plant is erect and grows to about 20-40 cm. Flowers are white with yellow centers. Chamomile has been used since the Roman empire. It was used as an anti-spasmodic and sedative. In folk medicine, chamomile is used for rheumatism and intestinal parasitism. Chamomile has also been used as a hair tint and cigarette flavoring. In veterinary medicine, the most common uses are as a natural wormer, sedative, and as a treatment for aggression. Chamomile contains essential oils, flavanoids, and hydroxycoumarins. Bisabolol, which accounts for 50% of the essential oils found in chamomile, has an acute LD50 of 15 ml/kg in rats and mice. Chronic ingestion in cats can cause epistaxis and hematomas due to the hydroxycoumarin content.

St. John’s Wort St. John’s wort (Hypericum perforatum) is also known as goatweed, rosin rose, and Klamath weed. Traditionally, this herb is used as an antidepressant, to treat diarrhea and gastritis. It was also used to treat insomnia and cancer. In veterinary medicine, this plant is well known for causing photosensitization in livestock and horses. St. John’s wort has been responsible for devastating economic losses. The major active constituents are anthraquinone derivatives, hypericin and pseudohypericin, as well as flavanoids.

Valarian root Valerian root (Valeriana officianalis) is one of the most popular herbs on the market. Common names include all-heal, heliotrope, Vandal root, and Capon’s tale. It is an herbaceous perennial found widely over the United States. The primary active ingredients are volatile oils, alkaloids, and most importantly, valepotriates. The root is the only part of the plant that is used. Valerian is classed as generally recognized as safe (GRAS) for food use. The volatile oils are used as flavoring in some food products. Valerian is used primarily as a sedative, and as a sleeping aid. It has also been used in epilepsy, headaches, colic, and numerous other minor ailments. Valerian is frequently taken as a tea, or as an extract. Valerian increases the length of sedation induced by pentobarbital and length of anesthesia produced by thiopental. Valerian has helped ease the effects of withdrawal from benzodiazepines due to similar receptor sites but increases the effects of sedatives if taken concomitantly. Most reports of adverse effects of valerian in human literature occur after chronic use. These effects include headache, cardiac arrhthymias, and agitation. In one case report, 200 mg in a human caused fatigue, tremors, abdominal pain, and mydriasis. Animal studies included injections of 50 mg/kg intravenous in cats which caused a drop in heart rate and blood pressure. Another study found no pharmacological effect in cats at 250 mg/kg. Mice given up to 4600 mg/kg orally produced mild clinical effects. Signs of toxicity included ataxia, hypothermia, and muscle relaxation. The ASPCA Animal Poison Control Center has had only a few calls on valerian ingestion. Most produced no clinical effects, although lethargy and sedation was seen in a cat.

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Garlic Garlic (Allium sativum) is most often used in cooking. Other common names include stinking rose, treacle, nectar of the gods, and camphor of the poor. The fresh bulb, dried bulb, and liquid extract of the bulb are all used. Historically, garlic has been used to treat diseases ranging from leprosy to clotting disorders in horses. Garlic powder used to be a standard tuberculosis treatment. The volatile oils in garlic contain the active ingredients, a sulfur containing compound and allicin. The majority of pharmaceutical activity is believed to be found in these substances. Garlic has been used to treat high cholesterol, hypertension, as well as the common cold and diabetes. Garlic is contraindicated if gastrointestinal ulcers or inflammation is present. Patients with hypothyroidism should also avoid garlic. It is theorized that consumption of high levels of purified active constituents may cause reduced iodine uptake by the thyroid. Due to increased clotting times, garlic should be avoided prior to surgery. Since garlic can have a hypoglycemic effect, insulin dosages should be monitored carefully. Anticoagulant effects of warfarin may be enhanced by garlic use and clotting times require additional monitoring. Garlic is in the same family as onions and a similar toxic effect would be expected. Onion toxicity results in weakness, tachypnea and tachycardia. Hematological changes including hemolysis, Heinz bodies, and possibly methemoglobinemia may occur.

Essential oils Essential oils are produced by a large number of plants. The oils are a mixture of terpenes and other chemicals. Essential oils are used from food flavorings to perfumes to medications. The most commonly used essential oils in veterinary medicine include Melaleuca or tea tree oil (Melaleuca alternifolia), pennyroyal oil (Mentha pulegium), D-limonene and linalool (Citrus spp.), Citronella (Cymbopgum nardus), Thuja (Thuja occidentalis), and wormwood or absinthe (Artemisia absinthium). In veterinary medicine, essential oils are most commonly used to treat flea infestations, hot spots or other dermatological conditions, or as wormers. Oils may be found in shampoos, dips, liniments, teas, tinctures, syrups, or other formulations. Cats appear to be more sensitive to essential oils than dogs. The most common clinical signs after dermal exposures include ataxia, muscle weakness, depression, and behavioral abnormalities. Severe hypothermia and collapse have occurred in cats. A transient paresis can occur in small breed dogs when melaleuca oil is applied down the spine as a topical flea treatment. Cats have developed scrotal dermatitis after exposure to D- limonene or linalool. Liver failure is associated with essential oils, especially pennyroyal and melaleuca. Oral ingestions cause vomiting and diarrhea. Central nervous system depression may occur, and seizures are possible with large doses. Aspiration pneumonia can occur when essential oils are inhaled. Death can occur with sufficient doses. Signs usually develop from almost immediately up to eight hours post exposure.

Grapefruit seed extract Grapefruit seed extract (GSE) is being touted as a disinfectant, to cure fungal disease, external parasites, and many other conditions. GSE is made from the pulp and seeds of grapefruit. The final product is acidic, and contains quaternary compounds similar to cationic detergents. Severity of injury typically depends on the concentration of the product and the duration of the contact. Primary clinical signs include hypersalivation, vomiting with possible hematemesis, muscular weakness. Fasciculations and CNS depression may occur. Diarrhea, dermal necrosis or dermatitis, pulmonary edema, and hypotension are possible. Corrosive burns can occur in the mouth, especially on the tip and sides of the tongue, pharynx and the esophagus. Hyperthermia is common in cats.

Summary When a decision has been made to use an alternative therapy, quality assurance is critical. Herbal medications should be treated as medications, with appropriate precautions. Veterinarians should encourage clients to discuss alternative therapies with them. Choice of therapies, diagnoses, and clients expectations should be discussed. Encourage clients to learn the facts behind CAM (complementary and alternative medicine) therapies. When discussing information obtained from web sites, suggest clients use the C.R.E.D.I.B.L.E. evaluation criteria developed by Dr. Gunther Eysenbach.: Current and frequent updates References cited Explicit purpose and intentions of the site Disclosure of sponsors Interests declared and not influencing objectivity (eg financial interests) Balanced content, listing advantages and disadvantages Labeled with metadata Evidence level indicated.

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Managing Toxicosis in Exotic Species Tina Wismer, DVM, DABT, DABVT ASPCA Animal Poison Control Center Urbana, IL

Our exotic animal pets can present a challenge with some of their differences in physiology. However, the same adage remains…treat the patient, not the poison. Take a complete history while the patient is being stabilized in the incubator with oxygen. The history should include information such as whether the animal has been exposed to infectious disease or toxins; the animal’s environment, diet, reproductive status, and previous illness; husbandry practices should be discussed. Environmental history includes information about caging, flight capabilities (in birds), and exposure to toxins. Most decontamination techniques transfer easily from one species to another. Stress is a big killer of our exotic animal patients. Taking it slow and allowing down time can help reduce stress. Sedatives and anesthesia can make managing decontamination much easier for you and the animal. Always check cheek pouches as they can hold large amounts of toxic substances. Clean out with a cotton swab until empty.

Emesis Do not induce vomiting in species that cannot vomit (rabbits, rodents, marsupials, birds, ruminants). It is OK to induce vomiting in pot bellied pigs and ferrets.

Adsorbents When administering charcoal by gastric tube to rabbits go slowly as their stomach is thin walled and could easily be ruptured. When giving activated charcoal to the avian patient, take into consideration the crop volume. Species Crop Volume (ml) Finch 0.1-0.5 Canary 0.25-0.5 Budgie 1 Lovebird 1-4 Cockatiel 2-4 Small Parrot 3-6 Medium parrot 10-15 Large Parrot 20-30

Cathartics Magnesium sulfate should not be used in reptiles as their slow GI transit time can allow large amounts of magnesium to be absorbed.

Glue traps Use oily substance (mineral oil, cooking oil, etc.) to break down glue. Remove oil with liquid dish washing detergent.

Toxic vapors Carbon monoxide (CO) Carbon monoxide (CO) is produced by inefficient combustion of carbon based fuels (wood, coal, petroleum, natural gas) and is toxic to all species of domestic animals, birds, and humans. CO will accumulate in garages, homes, closed trailers, and livestock housing units. It has a similar density to air, so it does not segregate or stratify readily. CO competes with oxygen for binding to hemoglobin. CO has 240 times the affinity of oxygen for hemoglobin. This higher affinity results in production of carboxyhemoglobin (COHb) over time. Acute CO poisoning results when COHb concentration in blood exceeds 30%. For dogs, 3700 ppm of CO for 1-2 hours produces 70% COHb with apnea and death. Birds (with high respiratory and metabolic rates) are generally more susceptible than mammals. Carboxyhemoglobin is readily detected in blood, and the test is available at many clinical laboratories, in hospitals and some veterinary diagnostic laboratories. Acute CO toxicosis causes rapid depression, coma, respiratory paralysis and death. The blood is bright red due to the inherent color of carboxyhemoglobin. The skin and mucous membranes may be pink. Anoxia causes necrosis of the cerebral cortex and white matter, globus pallidus and brain stem. Recovered animals can have permanent brain damage and locomotor impairment. COHb is very stable and this may prevent spontaneous recovery to oxyhemoglobin when CO exposure ceases. Hyperbaric oxygen is used in human medicine to drive CO from hemoglobin binding sites. If hyperbaric oxygen is available, it is the treatment of choice for our patients. If not available, place the animal in an oxygen rich environment until able to intubate and ventilate as needed with 100% oxygen. Carbon monoxide prognosis is guarded unless hyperbaric oxygen is available. Poisonings can be prevented in homes and animal confinement units with alarmed CO detectors.

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Polytetrafluoroethylene (PTFE, Teflon®) Although polytetrafluoroethylene (PTFE, Teflon®) is inert under ordinary circumstances, when the polymer is heated under conditions of inadequate ventilation, PTFE fumes may result. Small pet birds are extremely sensitive to chloroflourocarbon fumes, which sensitize the myocardium causing arrhythmias, pulmonary congestion and cardiac failure. With PTFE toxicosis, birds will show respiratory signs immediately. Most die quickly, but some may survive and die later. Environmental conditions and ventilation can be vastly different between rooms and homes. Birds that die may not be in the closest rooms to the PTFE source. Temperature (F) Common Cooking Temperatures 325 Birds died from preheated oven (Stewart, 2003) 350 Common baking temperature 396 Temperature of PTFE-coated light bulbs under which Missouri birds died (Boucher, 2000) 500 Searing temp for meat in oven or grill 536 Birds killed in DuPont lab experiments 700 Preheated grill 750 Surface of PTFE-coated pan after heating for 8 minutes on conventional stove (Wells, 1982) 1000 Drip pans (gas range) 1500 Broiling temperature for high-end ovens Smoke Smoke can be generated by the burning of many different substances. With smoke inhalation, dyspnea may be delayed several hours. Treatment is oxygen, bronchodilators and possibly diuretics. Other vapors Substance Where Found Clinical Signs Acetone Paints, solvents, cleaning agents CNS depression, narcosis, respiratory irritation. Excreted in expired air. Possible inhalation pneumonia. Benzene Paint and varnish removers Respiratory and dermal irritation; CNS depression; prolonged exposure may cause blood dyscrasia Heptane Waterproofing agents Dyspnea, pulmonary edema Mineral spirits Painting and refinishing solvents Dermal and GI irritation. Less volatile than toluene, xylene or naphtha Painter's naphtha Solvent for lacquers and fast drying CNS depression, ataxia. paints Toluene Anthelmintics, inks, dyes, varnishes, Ataxia, depression; cerebellar, liver and renal damage. paints, adhesives Xylene Thinners, rubber solvents, adhesives, Ocular and dermal irritation, impaired vision, tremors, salivation, coma. lacquers Other household items with strong fragrances or odors can all cause respiratory irritation in our small mammal and avian patients. Treatment for most of the animals is insuring good ventilation. Remove to fresh air and supply oxygen if needed. Remind owners to remove animals before using such products.

Heavy metals Lead Lead toxicosis, termed “plumbism,” has been recognized in both humans and domestic animals for thousands of years. All species of animals are susceptible to lead toxicosis, but it has been most commonly associated with waterfowl. Wildlife may still be exposed to lead from lead shot deposited prior to the ban or used to hunt upland game, from ingestion of lead sinkers or jigs lost by fishermen, from environmental contamination from lead smelters or sewage sludge, or from ingestion of tissue from prey containing lead shot or bullets. Captive wildlife and household pets may ingest lead from leaded paints or caulking in old facilities or on old machinery/equipment, from some galvanized containers, or from linoleum, any of which may unknowingly be present in their enclosures. Lead interferes with a variety of metabolic activities within the body, including red blood cell production, bone formation, nerve transmission, and immune function. Anemia and immunosuppression are common features of chronic lead toxicosis in humans and animals. Competition with calcium in the body results in lead being stored in the bone and also leads to alterations of nerve and muscle function. Interference with cell membrane-associated pumps results in cellular damage in the kidney, liver and myocardium. Lead may also cause reproductive dysfunction in a variety of species. The clinical signs of lead toxicosis will vary depending on whether the exposure is acute or chronic, and death may occur within a few days to several months depending on the degree of exposure (e.g. number of shot ingested). Acute lead toxicosis in mammals generally produces signs of gastrointestinal and CNS dysfunction. Affected mammals may develop anorexia, vomiting, diarrhea, lethargy, behavior disorders, hyperesthesia, ataxia, blindness, seizures, paralysis, coma and death. Avians develop an impacted crop. Treatment of lead toxicosis includes eliminating the metal from the gastrointestinal tract, chelation therapy to reduce blood lead levels, and general supportive care. Animals showing severe clinical signs should be stabilized as needed prior to institution of other therapies. Removal of lead objects from the gastrointestinal tract is necessary prior to attempts at chelation, as most chelators will 668

enhance lead absorption from the gastrointestinal tract and thereby increase blood lead levels if there is lead in the gut. Calcium EDTA, penicillamine and succimer (DSMA) can be used a chelators. Zinc Zinc is an essential mineral. Most commonly, animals are exposed through ingestion of zinc from objects such as carpentry hardware (e.g. nuts and bolts), US pennies, and galvanized containers. Zinc-containing objects in the stomach or gizzard are slowly corroded by the low pH, releasing zinc that is readily absorbed into the bloodstream. Zinc is directly damaging to red blood cells, resulting in hemolysis. Renal failure secondary to the hemolysis may develop. Because zinc is irritating to the gastrointestinal tract, vomiting may be noted for a few days prior to the onset of more severe signs. Animals may subsequently present with weakness, lethargy, pallor, ataxia and collapse. Radiographic identification of metallic foreign bodies in the stomach or gizzard may help in determining if zinc toxicity is possible. Bloodwork should be evaluated for evidence of anemia, hemoglobinemia, hemoglobinuria, and/or icterus. Serum zinc levels can aid in diagnosis, but turnaround times may be too long. Zinc levels over 200 ug/dl are considered diagnostic. Treatment of zinc toxicosis entails stabilizing the patient (blood transfusions, etc.) and removal of any metal from the gastrointestinal tract.

Pesticides Anticoagulant rodenticides The injectable Vitamin K1 can be given orally in our patients too small for the oral capsules/tablets. Pyrethrins Pyrethrin based sprays can cause seizures in snakes. Fish are also very sensitive to pyrethrins and they should not be used around fish tanks or ponds where run off could be a problem. OP/carbamates Reptile exposure to OPs or carbamates can cause signs similar to mammals: salivation, ataxia, muscle fasciculation, inability to right themselves, coma, respiratory arrest, seizures and death. Birds are also very sensitive to organophosphates. Treatment of OP/carbamate toxicity as also similar to mammals. Ivermectin Ivermectin cannot be used by injection in any of the chelonian species. The use of this medication will result in flaccid paresis or paralysis. Some lizards and snakes (ball pythons) may also show mild neurologic signs when treated. Prognosis for turtles/tortoises is poor. Fipronil (Frontline®) Seizures have been seen in rabbits a few hours up to 4-5 days post fipronil exposure. The mechanism of action is unknown. Once seizures begin prognosis is guarded. D-limonene D-limonene is found in citrus oil flea dips and is toxic to male rats. D-limonene causes renal failure in these animals by binding to α2u-globulins leading to protein accumulation in the renal tubules.

Medications NSAIDs Ferrets are the most likely exotic species to get into human medications. An acute ibuprofen overdose in ferrets is associated with GI, renal, and CNS (coma). Treatment is the same as for other species. Acetaminophen Ferrets have low levels of acetaminophen UDP-glucuronosyltransferase activity; only the cat has lower levels. Due to the ferret’s inability to detoxify acetaminophen, they should be decontaminated at the same doses as cats and treated the same. Venlafaxine Venlafaxine (Effexor®) is an antidepressant. Ferrets are attracted to the taste of this medication. Mydriasis, vomiting, tachypnea, tachycardia, ataxia and agitation are the most common signs. Acepromazine may be used for the agitation, and cyproheptadine may be useful in antagonizing the serotonin effects.

Plants Cardiac glycosides Oleander (Nerium oleander), foxglove (Digitalis purpura), Lilly of the valley (Convallaria majalis), dogbane (Apocynum sp.) and squill (Scilla [Urginea] maritima) all contain cardiac glycosides. The cardiac glycosides act like digoxin. The general symptoms of cardiac glycoside poisoning include diarrhea, abdominal pain, irregular pulse, tremors, and convulsions. In severe cases, death occurs. Some of our exotic patients do not have the same progression of signs. Rabbits, rodents (except the prairie dog), and reptiles did not have any GI signs, they went straight into heart failure. Treatment is supportive care, and Digibind® (Digoxin specific FAB fragments) may be used if arrhythmias are non-responsive to traditional medications.

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Avocado Avocados have been associated with toxicity. They cause sterile mastitis in mice, goats and other livestock and myocardial necrosis in birds and horses. Death occurs 24-47 hours post exposure. Insoluble calcium oxalate plants Plants of the Araceae family are a common cause of plant poisoning. They include dumbcane (Dieffenbachia sp), philodendron, elephant ear (Alocacia antiquorum), caladium, and Jack-in-the-pulpit (Arisaema sp). The plants contain calcium oxalate crystals which irritate mucous membranes and cause histamine release. Clinical signs may include oral pain and irritation, hypersalivation, head shaking, dyspnea, nausea, vomiting, and diarrhea. Treatment includes rinsing the mouth with milk to help precipitate the oxalates.

Mycotoxins Aflatoxins Avians are more sensitive to aflatoxins than other domesticated species. However, all mammals are susceptible. Aflatoxins are usually associated with cereal grains, corn and peanuts. Clinical signs include lethargy, weight loss, anorexia, ataxia, regurgitation and polydipsia. Long term ingestion can lead to liver cancer.

Other Lucibufagins (fireflies) Lizard deaths have been reported as happening after consumption of fireflies. Researchers have identified chemicals in fireflies that are related to their luminescence. Some of these chemicals are similar to digitalis. Avian botulism Avian botulism is a paralytic, often fatal, disease of birds resulting from ingestion of toxin produced by Clostridium botulinum. There are seven types of toxins (A-through G). Waterfowl die-off is usually from type C; sporadic die off among fish-eating birds (common loons, gulls) from type E toxin, and domestic chickens can be affected by type A. C. botulinum spores persist in the soil for years. Toxin production occurs during multiplication of the vegetative form when conditions are favorable (dead organic matter, lack of oxygen, temperature 75 F, pH 5.7-6.2, water depth). The toxin production takes place in decaying animal carcasses. Maggots concentrate toxin and the waterfowl eats the now poisonous maggots. Death of the waterfowl then perpetuates the cycle. The toxin affects peripheral nerves and results in paralysis of voluntary muscles and inability to fly and paralysis of leg muscles (early sign). Paralysis of the nictitating membranes and neck muscles follow. Death is from drowning or from respiratory failure. Prompt removal and proper disposal of carcasses is key in controlling the disease. Providing supportive care and antitoxin injections may provide 75- 90% recovery rate (high cost). Chlorine The use of chlorinated tap water without pretreatment with dechlorinating agents can create lethal chlorine levels which can kill all fish in the tank/pond within hours. Dechlorinator placed after the fact and water changes may help decrease mortality.

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Urine Pain: UTI Joe Bartges, DVM, PhD, DACVIM, DACVN Cornell University Veterinary Specialists Stamford, CT

Etiopathogenesis  Urinary tract is in contact with external environment and bacteria normally reside in distal urogenital tract  Urinary tract has many defense mechanisms to prevent bacterial urinary tract infection o Anatomically . Length of urethra . Presence of high pressure zones in urethra . Urethral and ureteral peristalsis . Vesicoureteral flaps . Extensive renal blood supply and flow o Mucosal defense barriers . Glycosaminoglycan layer . Antibody production . Intrinsic mucosal antimicrobial properties . Exfoliation of cells . Commensal non-pathogenic microbes in distal urogenital tract o Composition of urine . Concentration/osmolality . High urea nitrogen concentration . Organic salts . Low molecular weight carbohydrates . Tamm-Horsfall mucoprotein o Cell-mediated and humoral-mediated immunity o Frequent and complete voiding  A UTI also requires a pathogenic bacterial organism o Not all bacteria are pathogenic o For UTI, bacteria must possess 1 or more urovirulence factors for motility, adherence, invasion, production of enzymes, and production of toxins  Uropathogenic bacteria invade primarily from ascension from the lower urogenital tract

Physical examination findings and clinical signs  May be symptomatic or asymptomatic  Bacterial infection of the lower urinary tract is often associated with signs similar to other lower urinary tract diseases including hematuria, pollakiuria, dysuria, stranguria, and inappropriate urination  Bacterial of the upper urinary tract may be associated with hematuria o If septicemia develops, systemic illness may occur o May be associated with recurrent lower urinary tract infection and clinical signs  Bacterial urinary tract infections occur in 2-3% of dogs and in female dogs more often than male dogs o It is more common in older dogs  Bacterial urinary tract infections occur in <1% of cats o It is very rare in cats <10 years of age o It occurs in >40% of cats >10 years of age

Diagnosis  Urinalysis and urine culture  IT’S GOLD FOR A REASON ! o Urine should be collected by cystocentesis . Urine in the bladder is normally sterile or contains very low numbers of bacteria . The more distal in the urogenital tract, the larger the numbers of bacteria

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. Even if a single organism is cultured from a voided sample, it does not mean that a UTI is present or that is the offending organism o Always examine urine sediment . Pyuria (>5 WBC/hpf) is often present, unless animals are immunosuppressed . Identification of bacteria is helpful, but not accurate  Staining urine sediment improves predictive value Unstained Stained Sensitivity 82 % 93 % Specificity 76 % 99 % Positive Predictive Value 40 % 95 % Negative Predictive Value 96 % 99 %  Urine specific gravity should be normal; however, dilute urine may be a risk factor for development of bacterial urinary tract infection or may indicate infection of the upper urinary tract  Urine sediment examination may reveal struvite crystalluria associated with UTI  Struvite crystalluria, however, can be normal  We will discuss further with urolithiasis  Cylindruria may be present with upper urinary tract UTI  Cellular casts are always abnormal  Urine culture is most definitive means of diagnosing a bacterial urinary tract infection  Urine should be collected by cystocentesis  Urine should be transported in a sealed container and processed as soon as possible  If processing is delayed, refrigerate the sample  Alternatively, a blood agar plate can be streaked and later submitted for identification and antimicrobial susceptibility pattern if bacteria grow  Antimicrobial susceptibility testing  Kirby-Bauer agar diffusion test  After an organism is isolated and identified, it is transferred to an agar plate  Antimicrobial discs are placed on the plate  Zone of inhibition around the antimicrobial discs are measured to determine susceptibility of the bacterium  This is an inexpensive and readily available technique  However, concentration of antimicrobial on most discs are not similar to concentration of antimicrobial achieved in urine  Minimum inhibitory concentration  More sensitive and specific than Kirby-Bauer method  More expensive and more time consuming technique and not widely available  Lowest concentration required to inhibit bacterial growth  Performed using a series of dilutions of each antimicrobial in a multi-well plate to which a standard number of bacteria are added  Kirby-Bauer technique is acceptable for most bacterial urinary tract infections Common bacterial isolates 1  Escherichia coli is most common in dogs and cats accounting for /3 to ½ of infections  Gram positive organisms are second most common cause  Staphylococci and streptococci account for ¼ to 1/3of infections 1  Bacteria accounting for remaining ¼ to /3 of infections  Proteus spp., Klebsiella spp., Pasteurella spp., Enterobacter spp., Pseudomonas spp., Corynebacterium spp., and Mycoplasma spp.  Laboratory evaluation  Should be normal unless associated with septicemia, azotemia due to renal failure or dehydration, or predisposing metabolic disease (e.g. hyperadrenocorticism, diabetes mellitus, hyperthyroidism, etc)  Radiography, ultrasonography, endoscopy  Usually normal unless bacterial infection is associated with a predisposing cause  Struvite stones may form secondary to a urease-producing bacterial urinary tract infection  Renal pelvic and proximal ureteral dilation may be present with pyelonephritis

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Treatment  Treatment of bacterial urinary tract infection is dependent on whether the breech in host defenses is temporary or persistent UTI Antibiotic Therapy  Antimicrobial agents Intact male or female dog ?  Supportive care, if necessary Predisposing systemic and/or local factor(s) ?  Correct or control identifiable predisposing Recent previous UTI’s ? cause(s) Cat ?  Bacterial urinary tract infections can be classified as YES NO simple/uncomplicated, or complicated  Simple/uncomplicated bacterial urinary tract infection Treat for 4-6 weeks Treat for 10-14 days  Bacterial urinary tract infection with no based on C & S based on: underlying structural, neurologic, or functional C & S abnormality “Best guess”  Occurs in most dogs Redo C & S  Usually successfully treated with a 10-14 day - 5-7 days after start course of the proper antimicrobial administered at appropriate dose and frequency - Before stop o Recent study demonstrated - 5-10 days after start effectiveness of a 3-day course of once-a-day, high dose, enrofloxacin  Clinical signs should resolve and urinalysis results should improve within 2 days  Complicated bacterial urinary tract infection  Bacterial urinary tract infection associated with a structural, neurologic, or functional abnormality  Reproductively intact dogs, all cats, and animals with predisposing causes for bacterial urinary tract infections (e.g. renal failure, hyperadrenocorticism, diabetes mellitus, etc)  In addition, animals that have bacterial urinary tract infections that are relapses, reinfections, or superinfections  Pyelonephritis and prostatitis are examples of complicated bacterial urinary tract infections  Complicated infections should be treated for 3-6 weeks  Urine should be evaluated in the first week of treatment  Towards the end of therapy  5-7 days after discontinuing antimicrobial treatment  Relapse  Recurrence of a bacterial urinary tract infection with the same organism  Usually occur within days to weeks of discontinuing antimicrobial treatment  Possible causes include  Choice of inappropriate antimicrobial agent  Antimicrobial agent given at inappropriate dosage, frequency, or duration  Complicating factors  A urine culture should be evaluated prior to instituting antimicrobial treatment and further diagnostic testing is indicated  Reinfection  Recurrence of a bacterial urinary tract infection with a different organism than what was initially present  Usually occur weeks to months after cessation of antimicrobial treatment  Although predisposing factors may be present, many animals that become reinfected do not have identifiable risk factors  If reinfections are infrequent (<3 per year), then each episode may be treated as an uncomplicated bacterial urinary tract infection unless a predisposing cause is identified  If reinfections occur with greater frequency (>3 per year), then the animal should be considered as having a complicated bacterial urinary tract infection and treated accordingly  Diagnostic testing for predisposing cause(s) should be done if not performed previously  Prophylactic antimicrobial treatment may be warranted in these animals  Complicating factors for recurrent UTIs o Breaks in host defenses . Local defenses  Recessed vulva  Deep-seated infection: 18.5% of cases had positive bladder wall or urolith culture with a negative urine culture o In our experience, 4% of bladder wall cultures are positive in dogs with negative urine culture who do not have uroliths  Anatomic defects (e.g. ectopic ureter)

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 Indwelling urinary catheter o Concomitant antimicrobial administration decreases incidence of UTI o However, when UTI develops, it is highly resistant o We do not administer antimicrobial agents with an indwelling urinary catheter unless there is another reason . Systemic host defenses  Associated complicating disease (e.g. diabetes mellitus, hyperadrenocorticism, hyperthyroidism, renal failure) o Bacterial factors . Multi-drug resistance . Unusual organism (e.g. Corynebacterium, methicillin-resistant Staphylococcus)

Prevention  Minimize bacterial contamination of the urinary tract and avoid or minimize conditions that impair host defenses  Catheterization and endoscopy of the urinary tract always carries a risk of inducing a bacterial urinary tract infection o Magnitude of risk increases with degree of pre-existing urinary tract disease, amount of any additional injury caused by the procedure, and duration of the procedure o Risks can be decreased by being careful to perform invasive procedures only when necessary, by performing the procedure as atraumatically as possible, and by removing the catheter or endoscope as soon as possible o Catheter-induced bacterial urinary tract infection o Bacteria migrate along outside of catheter o Risk of bacterial urinary tract infection increases with pre-existing urinary tract disease o Risk is greater in animals with indwelling urinary catheters than in those that are intermittently catheterized o Despite the low risk, one study documented bacterial urinary tract infections in 7 or 35 dogs that were catheterized one time o Bacterial urinary tract infection occurs in>50% of animals after 4 days with an indwelling urinary catheter o Antibiotic treatment while an indwelling catheter is in place decreases the frequency of bacterial urinary tract infection; however, when infection occurs, the organisms exhibit a greater degree of antimicrobial resistance. . Therefore, do not give antimicrobials to animals with indwelling urinary catheters unless indicated for some other reason . Catheter-induced bacterial urinary tract infection may be minimized by . Using intermittent catheterization when possible . Removing indwelling urinary catheters as soon as possible . Using a closed collection system . Avoiding antimicrobial agent administration while catheters are inserted  Cats with perineal urethrostomies are at high risk for developing bacterial urinary tract infections  Resistant urinary tract infections Resistant E coli UTI – Several options may exist depending on results of culture and sensitivity  Flouroquinolones (e.g. Enrofloxacin: 5-20 mg/kg PO q24h): May be effective when used at high  Aminoglycosides: Are often an effective antimicrobial agent. Amikacin (cats: 10-15 mg/kg IV, IM, SQ q24h; dogs: 15-30 mg/kg IV, IM, SQ q24h) appears to be less associated with nephrotoxicity than gentamycin, but should not be given to animals with azotemia. It can be administered by owners at home  Potentiated beta-lactams: may be tried if intermediate susceptibility is present. I usually use amoxicillin-clavulanic acid at a higher dosage (22 mg/kg PO q12h). Ampicillin-sulbactam may also be used (cats - 20-30 mg/kg PO q8-12h x 3-7 days; 5- 11 mg/kg IM, SQ q8-12h; has been given 20-40 mg/kg IV q6-8h; dogs - 12.5 – 30 mg/kg PO q8-12h x 7 days; 6.6 -40 mg/kg IM, SQ q16-2h x 3-7 days; has been given 20-40 mg/kg IVq6-8h)  Penems: Meropenem may be useful for highly resistant (8 mg/kg SQ q12h)  3rd generation cephalosporins: May be useful. Cefpodoxime (Simplicef) does not have as much activity as parenteral forms and may not be effective even with a favorable sensitivity pattern (5-10 mg/kg PO q24h)  Cefovecin: A newer parternal long-acting cephalosporin has been shown to be effective against E coli in dogs and cats; however, effectiveness with resistant organisms is unknown (8 mg/kg SQ q14d)  Staphylococcus UTI (methicillin resistant) – These appear to be more difficult to treat. With resistance to methicillin, beta lactam antibiotics even potentiated ones will not be effective. Staphylococci are inherently resistant to fluoroquinolones (as are most Gram positive cocci) even with a favorable sensitivity pattern.  Chloramphenicol: monitor liver enzymes as can be hepatotoxic, GI side effects occur commonly (50 mg/kg PO q8h)  Linezolid: An oxazolidinone antibiotic with activity against Gram + organisms. It is often effective against methicillin- resistant Staphylococci, but is expensive (10 mg/kg PO q12h)  Vancomycin: Standard for treating methicillin-resistant Staphylococci, it is discouraged from being use because of potential for inducing resistance that may spread to human medicine (15 mg/kg IV q8h)

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Enterococcus Oftentimes Enterococcus UTI is not associated with clinical signs and there is suggestion that not treating may be better than treating. In some animals without clinical signs or urinalysis changes (pyuria, hematuria), no treatment with re-culture in 2 weeks may reveal eradication of the organism. Treatment should be considered for animals with active clinical infection or that are immunocompromised.  Penicillins: may be sensitive to amoxicillin/ampicillin especially potentiated ones at higher dosages  Inherently resistant to cephalosporins, flouroquinolones, trimethoprim-sulfa, erythromycin even if favorable sensitivity results  Can combine amikacin with a penicillin  Penems may be effective for E faecalis, but not E faecium infections  Linezolid and vancomycin may be effective  There is evidence that if a resistant UTI is not associated with clinical signs, that it may be better to not treat. Prophylactic antimicrobial treatment may be indicated in animals with relapses or frequent reinfections  Antimicrobial agent should be chosen based on urine culture and susceptibility pattern 1  The agent is administered at ½ to /3 of daily therapeutic dose and is usually given at night  Urine should be re-cultured every 4-6 weeks  If a “break through” infection does not occur during a 6 month period, then antimicrobial treatment can usually be discontinued  Disadvantages of this approach include development of resistant bacteria and side effects of the antimicrobial agent Methenamine is an effective preventative in select cases  It is a cyclic hydrocarbon that is hydrolyzed to formaldehyde at pH < 6.5  It is combined with an acidifying salt either hippurate (D: 500 mg PO q12-24h); C: 250 mg PO q12-24h) or mendelate (D, C: 10 mg/kg PO q6-12h) but additional acidification may be required  It is effective against many organisms, but may cause systemic acidosis because it has acidifying properties  It should not be used with renal failure Nitrofurantoin (4 mg/kg PO q6-8h; prophylaxis: 3-4 mg/kg PO q24h)  Has activity against many organisms  Is not used much in veterinary medicine; therefore, susceptibility is high  Complications include GI upset, hepatopathy, peripheral neuropathy Estrogens  May be helpful in female dogs with recurrent vaginocystitis  May increase epithelial turnover keeping bacterial counts down  No data  Dose as with incontinence o Estriol: Start at a dose of 1 mg/dog PO q24h. If treatment is successful reduce the dose to 0.5 mg/dog PO. q24h. If treatment is unsuccessful increase to 2 mg/dog PO q24h. Alternate-day dosing can be considered once a response has been seen. The minimum effective dose is 0.5 mg/dog PO q24-48h. The maximum dose is 2 mg/dog PO q24h o Premarin: 20 ug/kg/d x 7 days; then q2-3d PO o DES: 0.1-1 mg/day x 5 days; then q3-7d PO  Complications are uncommon Urinary acidifiers do NOT work for prevention of bacterial UTI in dogs and cats  Bacteria can live in pH values of 4.0 to 9.0  Dogs and cats cannot achieve urine pH values of < 5.5 or > 9.0  Therefore, it is not physically possible to acidify urine enough to prevent UTI’s Ecotherapeutics  Ecotherapeutics include probiotics (live bacteria) and probiotics (fiber sources that select for certain strains of bacteria)  The idea is to populate the GI tract with non-pathogenic “healthy” bacteria such as Bifidobacteria spp or non-pathogenic enteric bacteria  Since bacterial UTI originate from distal urogenital tract bacteria and since these bacteria are primarily enteric bacteria, the premise is that changing the intestinal flora will result in changing of the distal urogenital tract bacteria  These bacteria are not as “hearty” as the pre-existing normal bacteria; therefore, it is necessary to continue probiotics once you start  There is minimal evidence that this aids in preventing UTI’s; however, it does seem to help some dogs  There are several veterinary probiotics (Forti-Flora, Prostora Maxx, ProViable); however, there are many more human probiotics. 675

o There is really no such thing as a “dog” or “cat” specific probiotic o Usually want large numbers and multiple organisms o VSL #3 contains most organisms and multiple organisms (450 billion per packet; 1/10 packet per 4.5kg) Cranberries and cranberry extract  The active ingredient in cranberries are proanthocyanidins  Proanthocyanidins are found in cranberries, blueberries, and chocolate; however, only the proanthocyanidins found in cranberries are useful with bacterial UTI  Proanthocyanidins bind to adhesins, primarily PapG pili, that are virulent factors involved with binding of the bacteria to uroepithelial cells  PapG pilli are found on 25-50% of canine E coli, but not with other bacteria  Therefore, proanthocyanidins might be helpful in preventing certain strains of E coli from binding to uroepithelia, but not all E coli and not all bacteria  There is evidence in human medicine (nearly 2 dozen positive randomized, controlled clinical trials), but one study in dogs failed to show benefit; nonetheless, some dogs may benefit from proanthocyanidins found in cranberry extract D-mannose is a sugar that may prevent bacterial adherence. It is also incorporated into the GAG layer and may prevent bacterial invasion into uroepithelial cells. We use Pure Encapsulation d-mannose at 1/8 (1/16 tspn) scoop for small dogs and cats, 1/4 scoop (1/8 tspn) for medium dogs, and 1/2 scoop (1/4 tspn) for large dogs q8h.

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Urine Agony: Urolithiasis Joe Bartges, DVM, PhD, DACVIM, DACVN Cornell University Veterinary Specialists Stamford, CT

 Urolithiasis is common in dogs and cats  99% of uroliths occur in the lower urinary tract  Urolith formation is not a specific disease, but the sequelae to a group of underlying disorders  Urolith formation occurs with sustained alterations in urine composition that promotes supersaturation of one or more substances in urine resulting in precipitation and subsequent organization and growth into uroliths  Urolith formation is erratic and unpredictable emphasizing that several interrelated physiologic and pathologic factors are often involved  Mere presence of uroliths, however, does not necessitate their removal  Approximately 98% of uroliths occur in the lower urinary tract  Composition of uroliths  Approximately 80% of canine uroliths and 90% of feline uroliths are either struvite or calcium oxalate  Calcium oxalate and struvite occur at approximately even frequency although struvite occurs more commonly now (slightly)  The third most common type of mineral is urate  Other types – including compound uroliths (uroliths composed of more than 2 minerals) occur less frequently  Urolith formation is dependent on a combination of many factors  Urine pH  State of saturation – related to concentrations of minerals in urine  Inhibitors and promoters of urolith formation  Complexors  Macrocrystalline matrix

Struvite urolithiasis  Infection-induced struvite are the most common form occurring in dogs; whereas sterile struvite is the most common form occurring in cats o However, any animal that develops a bacterial urinary tract infection with a urease-producing micro-organism can develop infection-induced struvite uroliths o Sterile struvite uroliths have been documented to occur in dogs, but it is very rare Dogs  Struvite uroliths typically, but not always, form in female dogs (because of their higher risk for development of a bacterial urinary tract infection), and in dogs with immunosuppressive diseases or receiving immunosuppressive therapy because of their increased risk for bacterial urinary tract infections.  They can occur at any age, but are more common in young adult dogs.  They are the most common type of urolith in puppies (dogs < 1 year of age) Cats  Sterile struvite is the most common type of struvite urolith occurring in cats. o It typically occurs in young adult cats. o In older cats (>10 years) and in kittens (<1 year), infection-induced struvite urolith formation is more common than formation of sterile struvite uroliths because of their increased risk for development of a bacterial urinary tract infection  Remember, crystalluria is not synonymous with urolithiasis. o In healthy dogs, more than 50% of urine samples will contain struvite crystals without a bacterial urinary tract infection and without subsequent urolith formation o Likewise, some animals with active stone disease will not have crystals; however, most animals with active struvite stone disease will be crystalluric “Guesstimation” that is consistent with struvite uroliths  Urine pH: alkaline  Crystals: struvite  Bacterial urinary tract infection: 677

o Yes, if infection-induced struvite uroliths o Should be a urease-producing micro-organism . Typically Staphylococci spp . Occasionally Proteus spp . Rarely other bacteria such as Klebsiella and Streptococcus . Rarely Mycoplasma/Ureaplasma . Never Escherichia coli o No, if sterile struvite . Unless a secondary bacterial urinary tract infection has occurred  Radiographic appearance o Density: radiodense o Size: . Infection-induced: typically variable sized including some fairly large stones . Sterile: typically small (<5-10 mm) o Surface contour: typically smooth o Shape: . Infection-induced: often pyramidal shaped, similar to river rocks . Sterile: usually round, but can be wafer-like o Number: . Infection-induced: usually many dozen . Sterile: usually small number (perhaps 1-a dozen or so)  Serum and urine biochemical analysis o Often normal, especially in cats o In animals with infection-induced struvite, predisposing metabolic causes for bacterial urinary tract infection may be present . Cushing’s disease . Diabetes mellitus . FeLV/FIV  Signalment o Infection-induced: . Young to middle-aged adult female dogs . Pediatric or geriatric dogs and cats (due to predisposition to bacterial urinary tract infection . More common in females than males o Sterile: . Usually young adult cats (same is true in the few reported cases of dogs) . No gender or breed predisposition

Etiologic and pathophysiologic points Infection-induced struvite  A urinary tract infection with urease-producing bacteria (usually Staphylococci and Proteus spp; rarely other bacteria and Ureaplasma/Mycoplasma) occurs o Results in urease-mediated metabolism of urea to ammonium and carbonate  Ammonium comes from the ammonia liberated from urea buffering hydrogen ion in urine o Results in an alkaline pH o Changes ionization state of phosphorous  Magnesium is typically present in low amounts in urine  Phosphorous is present in high amounts and is a strong and important buffer (in acid-base metabolism) called “titratable acid” 2+ + 3-  These conditions favor formation of uroliths containing struvite (Mg NH4 PO4 ), with some “contaminant” minerals: calcium apatite and carbonate apatite  Struvite is less soluble (more likely to precipitate) when the urine pH is > 6.8, and is more soluble (more likely to stay in solution) when the urine pH is < 6.8  REMEMBER: these are called infection-induced struvite stones

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Sterile struvite  Sterile struvite typically forms in cats; however, it has been reported to occur rarely in dogs  Sterile struvite uroliths are typically composed of 100% struvite and do not contain “contaminant” minerals  The mechanism(s) for sterile struvite formation is not clear, although an alkaline urine pH is necessary o Persistent or recurrent alkaluria is a predisposing risk factor for sterile struvite formation o Because of the carnivorous nature of cats, a “post- prandial alkaline tide” occurs and can be profound . It is thought that with a high protein intake, a large amount of HCl is produced and excreted into the gastric lumen to begin digestion of protein (acid-mediated proteolysis) . This results in a metabolic alkalosis . Kidneys respond by excreting less acid and more base . This results in alkaluria . This is the reason most cat foods are “acidifying” – to minimize the post-prandial alkaline tide and prevent struvite formation  Other factors have a role o Highly concentrated urine resulting in retention of urine and concentration of calculogenic minerals o High levels of magnesium and phosphorous in urine

Therapeutic points  Overview of therapy o Eliminate existing uroliths o Eradicate or control bacterial urinary tract infection o Prevent recurrence of uroliths Surgical removal – Will be discussed later Minimally invasive procedures – Will be discussed later Medical dissolution Infection-induced struvite  Can be dissolved medically, or removed physically (surgery or voiding urohydropropulsion) – or combinations  Protocol: o Control and/or eradicate the bacterial urinary tract infection o Choose appropriate antibiotic o Must be administered during entire time of medical dissolution. Bacteria are trapped in matrix of urolith and released as the stone dissolves from the outer layers inwards (similar to an ice cube melting in a glass of water) o The struvite dissolution diet induces a diuresis, which may decrease efficacy of antimicrobial (although rarely are changes in dosage necessary) o Calculolytic diet (struvitolytic diet) o Currently, only 1 diet has data documenting its efficacy in medical dissolution of struvite – Hill’s Prescription Diet s/d o Diet is:  Lower in protein (source of urea and therefore ammonia)  Lower in magnesium  Lower in phosphorous  Acidifying  Diuresis (to stimulate thirst and urine output)  Although infection-induced struvite stones may dissolve with antibiotic therapy alone, it takes much longer than the combination of antibiotic and struvitolytic diet, and is less successful  Average time for dissolution is 8 weeks 679

o Monitor animal every 4 weeks o Urinalysis – should find aciduria, no crystalluria, no inflammation o Urine culture, if necessary o Survey abdominal radiography (at least a lateral view) to monitor dissolution  Dissolution therapy should continue for 2-4 weeks beyond radiographic evidence of dissolution of uroliths to ensure all stones are dissolved  Complications of medical dissolution o Recurrent urethral obstruction o Continued clinical signs of lower urinary tract disease (although signs typically resolve, except for polyuria/polydipsia, within 3-5 days of starting dissolution therapy) o Reaction to antimicrobial o Problems with diet  A very low protein diet – protein malnutrition may develop  Prolonged feeding of diet – it is not intended for long term consumption  Use cautiously if at all in pediatric patients, especially those in rapid growth phase  Contra-indicated in pregnant animals  Usually see an increase in alkaline phosphatase activity and a decrease in blood urea nitrogen concentration because of the low protein content  In addition to pregnant animals, contraindicated in:  Hypertensive patients or those that cannot tolerate a sodium load  Those with renal failure – acidifying, hypokalemia  Animals that cannot tolerate a high fat intake – diet is high in fat An alternative dissolution protocol has been shown to be effective in > 80% of dogs  In this protocol, the diet is not changed; instead a urinary acidifier (d,l-methionine; D: initial 100 mg/kg PO q12h) is administered in combination with an appropriate antibiotic for the organism responsible for struvite formation (typically Staphylococcus)  Dissolution occurs in 4-8 weeks  Advantage is that the diet does not require changing and the acidifier is safe  Disadvantage is that in the one study, 2 dogs had a shell of calcium phosphate that appeared to impede dissolution – this could be due to “over” acidification Sterile struvite  Can be dissolved medically or removed physically  Protocol: o Feed struvitolytic diet o Antimicrobials are not necessary unless a secondary infection is present (one that would not be associated with struvite formation) o Other aspects are similar to management of infection-induced struvite uroliths  Sterile struvite uroliths typically dissolve in 2-4 weeks; therefore, at recheck at 4 weeks, uroliths may no longer be visible on survey abdominal radiographs o Feed diet for 2 to 4 weeks beyond medical dissolution Prevention of struvite uroliths  Successful prevention of struvite uroliths involves modifying risk factors to decrease risk of re-formation Infection-induced struvite o Most important component of prevention is preventing the bacterial urinary tract infection o REMEMBER: these are called infection-induced struvite o If predisposing risks for recurrent bacterial urinary tract infections cannot be modified, then treat the animal as having a complicated bacterial urinary tract infection, and take appropriate prophylactic steps (see notes on urinary tract infections) o Dietary modification for prevention of infection-induced struvite uroliths is not warranted, and often not successful Sterile struvite  Dietary modification is often required to decrease risk of recurrent sterile struvite urolith formation  Specific struvite preventative diets are modified to decrease risk

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Calcium oxalate Calcium oxalate accounts for 40-50% of all uroliths and > 85% of nephroureteroliths Risk factors for calcium oxalate formation  Increased urinary calcium excretion (hypercalciuria) o May result from hypercalcemia, GI hyperabsorption (excessive absorption of calcium from the GI tract), resorptive (excessive calcium resorption from bone), or renal leak (decreased calcium reabsorption from the distal tubule)  Increased urinary oxalate excretion (hyperoxaluria) o May result from excessive absorption from the GI tract, excessive absorption from the GI tract due to deficiency of Oxalobacter formigenes (an enteric bacterial organism that metabolizes oxalate in the GI tract), and possibly from vitamin B6 deficiency (vitamin B6 is involved with oxalate metabolism)  In a small study of Miniature schnauzers, GI hyperabsorption appears to be the most likely cause as urinary calcium excretion decreased with fasting  Net result of risk factors is urinary oversaturation with calcium oxalate Signalment  Cats o Middle-aged or older o Males = females o Long-haired cats; Siamese and Ragdolls tend to form at young age o Overweight to obese body condition  Dogs o Middle-aged or older o Males > females o Small breed dogs (e.g. Miniature schnauzers, Lhasa apsos, Yorkshire terriers, Bichons). Bichons tend to form at young age o Overweight to obese body condition  Laboratory evaluation  Aciduria  Hypercalcemia o 20-35% of cats – usually idiopathic hypercalcemia o 4% of dogs – usually primary hyperparathyroidism  Crystalluria – not present in > 50% of cases with active stone disease  Renal azotemia – associated with nephroureteroliths Management  Medical protocols that will promote dissolution of calcium oxalate uroliths are currently unavailable; therefore, uroliths must be removed physically  If urethral obstruction is present, uroliths should be retropulsed into bladder and removed o If necessary urethrotomy or urethrostomy may be performed  If no clinical signs, then minimize growth in size and number and monitor for urethral obstruction and clinical signs  Removal of calcium oxalate uroliths o Surgery – cystotomy and / or urethrotomy / urethrostomy o Catheter-assisted retrieval  Technique can be used to retrieve “sand” or small uroliths  Uroliths must be small enough to pass through the internal diameter of the lumen of the urethral catheter  It is important to “jiggle” the urinary bladder to get the sand/uroliths “in motion” in order to facilitate retrieval through the catheter  Complications  Occur very rarely  Iatrogenic bacterial urinary tract infection is most likely complication that might occur  Irritation from catheterization resulting in urethral spasm and lower urinary tract signs may also occur, but they occur rarely o Voiding urohydropropulsion  Voiding urohydropropulsion is a non-surgical technique for removing bladder stones from dogs and cats  The technique is based on the idea of using gravity to assist an animal in voiding out stones

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 Indications  The largest diameter stone must be able to pass through the urethra at its narrowest luminal diameter  We have retrieved stones with the following sizes:  10 mm - 7.4 kg F / S K9  5 mm - 9 kg M / C K9  5 mm - 4.6 kg F / S Fel  1 mm - 6.6 kg M / C FelIt will not work in animals that present with urethral obstruction  Contraindications o Animals that present with urethral obstruction due to stones o Animals that have urethral outflow obstruction such as strictures, tumors o Do not perform in animals that have had a cystotomy in the previous 14 days – the bladder incision may not be strong o Use caution when applying pressure on the bladder in animals with a bacterial cystitis as this may cause reflux of infected urine up the ureters into the kidneys o Animals with other more serious disease should be stabilized or treated o Complications o Hematuria occurs commonly  In dogs, this usually subsides in a couple of hours  In cats, this may persist for 12-24 hours o Urethral obstruction may occur if one or more stones are larger than the smallest diameter of the urethra o Bacterial urinary tract infection occurs uncommonly, but may occur secondary to poor technique and urethral catheterization o Bladder and/or urethral rupture could occur, but is very rare  Voiding urohydropropulsion can be used in combination with other treatment modalities for bladder stone disease o Stones amenable to medical dissolution can be dissolved to a size where they can be retrieved using voiding urohydropropulsion o Stones that are accidentally left behind at surgery may be retrieved with this technique if they are small enough o This technique can be done at time of induction for a cystotomy. If all stones are retrieved then the animal can be recovered. If not, then proceed with cystotomy. Cystoscopy and retrieval and laser lithotripsy  Cystoscopy can be performed using rigid cystoscope (in female dogs and cats) or flexible cystoscope (in male dogs)  A small “semi-rigid” cystoscope is available for use in male cats; however, due to its size (1 mm) there is no operating channel  This permits visualization of the lower urogenital tract  Procedures such as biopsy, urolith retrieval, injections, and use of laser can be performed through the operating channel  In larger male dogs, a flexible endoscope may be used for visualization  In female cats and dogs, a 1.9mm, 2.7mm, or 4.0mm rigid cystoscope is used  I perform cystoscopy usually with the patient in dorsal recumbency  Requires general anesthesia  Fluid for instillation through the scope for distention of the lower urogenital tract and for visualization Cystoscopic retrieval of uroliths  Baskets and graspers can be inserted through the operating channel of the cystoscope for removal of uroliths  They must be small enough to be extracted through the most narrow portion of the urethra Laser lithotripsy  Laser lithotripsy can be used to manage bladder stones  Cystoscopy is performed and a laser fiber – usually a Ho:YAG laser – is inserted through the operating channel  The laser energy is used to fragment the stone into small fragments that can be retrieved  Complications are rare; however, trauma and perforation of the urinary bladder has been reported Cystoscopic-assisted cystotomy  A cystoscopic-assisted cystotomy is similar to laparoscopic removal  A small incision is made on ventral midline o In male dogs, the incision is made just cranial to the preputial reflection  The urinary bladder is grasped and brought to the incision edge of the linea where it is sutured with a continuous pattern of 2-0 or 3-0 Monocryl  A stab incision is made and a rigid cystoscope is inserted into the urinary bladder

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 Stones are retrieved using instruments passed through the cystoscope  The urinary bladder is closed with a single layer of 2-0 or 3-0 Monocryl, the linea closed with 2-0 or 3-0 PDS, and the skin and SQ closed with 2-0 or 3-0 Monocryl in a continuous intradermal pattern  Patients go home the same day Prevention  Calcium oxalate uroliths are recurrent; therefore, preventative measures are warranted  @ 8% recurrence at 6 months  @ 35% recurrence at 1 year  Recurrence increases with subsequent years  “Pseudorecurrence” refers to leaving uroliths behind after a procedure is performed  Occurs in 15-20% of cystotomies With hypercalcemia, potential causes should be investigated.  4% of dogs with calcium oxalate uroliths have hypercalcemia – usually due to primary hyperparathyroidism  20-35% of cats with calcium oxalate uroliths have hypercalcemia – usually idiopathic in nature Management The goal of prevention is lower the urinary saturation for calcium oxalate by decreasing urinary levels of calcium and oxalate and by increasing urine volume in order to dilute the minerals Cats with hypercalcemia  Feed a high fiber, mineral restricted diet  Administer an alkalinizing agent (Potassium citrate)  Citrate is an inhibitor of calcium oxalate crystallization and formation  In cats with idiopathic hypercalcemia, we have had success feeding a higher fiber diet (Hill’s Prescription Diet Feline w/d) and administering potassium citrate (see below) Cats without hypercalcemia  Feed a diet that induces a diuresis, is mineral restricted, and induces a neutral to alkaline urine pH  There are several “multiple use” feline diets formulated to prevent struvite and calcium oxalate  Prescription Diet c/d Multicare  Royal Canin S/O  Purina CNM UR st/ox  S/O and UR are higher in sodium than c/d  In a study comparing these 3 diets, they each induced a similar degree of urine undersaturation with calcium oxalate albeit by different mechanisms  Data from clinical studies is lacking, although in one clinical study of 10 cats with naturally-occurring calcium oxalate bladder stones, consumption of Prescription Diet Feline c/doxl decreased urinary saturation level to the low end of the metastable range  Data from healthy, non-urolith-forming cats have demonstrated decreased urinary saturation with calcium oxalate when cats consumed c/doxl or S/O Dogs  Feed a diet that is mineral restricted, diuresing, and alkalinizing  Prescription Diet U/d  This is an “ultra-low” protein diet originally formulated for “uremic” dogs  It is also low in minerals, has increased vitamin D, has increased B vitamins, and is very alkalinizing  Royal Canin S/O  Royal Canin s/o has been shown to decrease urine saturation with calcium oxalate but no clinical studies have been done  These diets are higher in fat than maintenance foods.  Can feed a higher fiber diet and administer the alkalinizing agent, potassium citrate Pharmacologic management Potassium citrate (initial: 75 mg/kg PO q12h)  Citrate is an inhibitor of calcium oxalate crystal formation because it forms a soluble salt with calcium  Oral potassium citrate may be beneficial in managing calcium oxalate uroliths because it is a calcium oxalate inhibitor and because it is alkalinizing in nature  Dosage is titrated to achieve a urine pH of approximately 7.5  Calcium oxalate preventative diets contain potassium citrate

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Vitamin B6 (2-4 mg PO q24h)  Vitamin B6 increases metabolism of glyoxylate, a precursor of oxalic acid, to glycine  Whether vitamin B6 deficiency occurs in adult animals, especially cats, with calcium oxalate uroliths is unknown, but unlikely  One study in adult calcium oxalate forming dogs showed lower plasma B6 levels when compared with non-urolith forming dogs  Vitamin B6 supplementation is inexpensive and safe and should be considered in pets that have difficult to control uroliths Thiazide diuretics (hydrochlorothiazide: 1-4 mg/kg PO q12h; chlorothiazide: 20-40 mg/kg PO q12h)  By inducing a diuresis and decreasing urinary calcium excretion, thiazide diuretic administration may be beneficial in pets with difficult to control calcium oxalate uroliths  Thiazide diuretics decrease urinary calcium excretion in human beings, dogs, and cats  In cats, thiazide diuretics have been shown to decrease urinary saturation for calcium oxalate in healthy cats only and they appear safe.  One 2-week study in calcium oxalate urolith forming dogs demonstrated decreased urinary calcium excretion  Diuretic administration may also be associated with dehydration and electrolyte imbalances and should be used cautiously in animals with renal failure Other agents  Glucocorticoids have been recommended to decrease blood calcium concentrations in cats with idiopathic hypercalcemia; however, they do so by increasing urinary excretion  Bisphosphonates have been recommended for cats with idiopathic hypercalcemia; however, no studies have been published.  Alendronate (2 mg/kg PO q7d; most cats respond to 10 mg total dose. Administer at least 6ml of water after administration and butter lips to increase salivation and increase transit as esophagitis and stricture may occur. Beneficial effect usually seen in 3-4 weeks.

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Urine a Mess: Micturition Disorders Joe Bartges, DVM, PhD, DACVIM, DACVN Cornell University Veterinary Specialists Stamford, CT

1. Micturition refers to the process of storing and periodically voiding urine. a. Disorders of urine storage usually lead to urinary incontinence, whereas disruption of urine voiding leads to incomplete emptying, dysuria, or urine retention b. Micturition is a complex integration of central, sympathetic, parasympathetic, and somatic nervous systems, with resultant muscular activity c. The two functional units of the lower urinary tract include the reservoir/pump (urinary bladder) and the continence/conduit (urethra). d. The urinary bladder and proximal urethra are composed of smooth muscle and are thus under autonomic nervous system control while the distal urethra is composed of skeletal muscle and thus under somatic nervous system control BOTTOM LINE: PARASYMPATHETIC PROMOTES PEEING SYMPATHETIC STIMULATES STORAGE 2. Disorders of micturition a. Several different ways of classifying i. Storage vs voiding ii. Full bladder vs empty bladder iii. Neurogenic vs myogenic b. Important to establish status of urinary bladder contractile force and patency of urethral outlet, determine whether disorder is primarily neurogenic or myogenic, and determine underlying etiology or contributing factors i. History and signalment 1. Age 2. Gender 3. Reproductive status 4. Prior neurologic disease 5. Trauma or surgery to urinary tract or nervous system 6. Water intake 7. Urination habit ii. Physical examination 1. Complete examination 2. Complete neurological examination a. Mental status b. Gait c. Spinal reflexes d. Cranial nerve reflexes and responses 3. Examine external genitalia 4. Bladder size and tone prior to a voiding urination 5. Digital rectal exam (all dogs; cats if sedated) 6. Digital vaginal exam (dogs; cats if sedated) 7. Observe urination if possible a. Does animal sense when bladder is full? b. Does it posture appropriately to void? c. Is urine stream normal? d. Does animal continue to attempt to void after stream has stopped? e. How does urinary bladder palpate after voiding? iii. Diagnostic testing 1. Urinalysis and urine culture 2. +/- CBC, serum biochemical panel 3. +/- Infectious disease testing (FeLV, FIV, etc) 4. +/- Imaging a. Survey radiographs b. Contrast studies c. Ultrasound 5. +/- Cystoscopy or exploratory 6. +/- Neurologic testing

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a. Myelogram b. MRI or CT 7. +/- Urinary system functional testing a. Cystometrogram b. Urethral pressure profile c. Problems with storage i. Bladder overactivity 1. Due to “hyperexcitability” of storage phase -> results in inability to permit adequate bladder filling because of “urgency” a. Animals have increased frequency of urination, pollakiuria, inappropriate urination b. Often urethral irritation or spasm is present c. Examples: cystitis, urocystolithiasis, chemical stimulation (cyclophosphamide) 2. Treatment: RELAX bladder a. Antimuscarinic agents (propantheline, oxybutynin, tolterodine) and antispasmodic agent ( oxybutynin, flavoxate, tolterodine) i. Decrease detrusor activity and have urethral anti-spasmodic effects ii. May help with refractory incontinence by increasing urine storage b. Tricyclic antidepressants: imipramine, amitriptyline (?) i. May improve bladder storage by several mechanisms including anticholinergic, alpha-adrenergic, and beta-adrenergic effects ii. Bladder atony 1. Due to neurogenic or myogenic causes a. “Upper motor neuron bladder” b. Bladder overdistention c. Animal may or may not posture to urinate with a distended bladder 2. Treatment: STIMULATE bladder (Should almost always relax urethra at same time) a. Manage large over-distended bladder with urinary catheterization b. Bethanechol i. Parasympathomimetic with direct cholinergic activity ii. Stimulates or augments smooth muscle contraction c. Metoclopramide? d. Cisapride? e. When pharmacologically stimulating bladder contraction consider relaxing urethra f. Manual expression d. Problems with voiding i. Increased outlet resistance 1. Functional vs mechanical a. “Upper motor neuron” lesion b. Urethral spasm c. Outlet obstruction (mass, stone, etc) d. Animal often postures to urinate but cannot void or voids a small amount 2. Treatment: RELAX urethra a. Manage large over-distended bladder with urinary catheterization b. Alpha adrenergic antagonists: phenoxybenzamine, prazosin i. Sympatholytics ii. Tamsulocin is used in humans and experimentally in dogs at 1-100 ug/kg IV and PO. Dosage of 1-10 ug/kg produced effect – consider 10 ug/kg PO q24h c. Skeletal muscle relaxants: diazepam, dantrolene, baclofen i. NOTE: external urethral sphincter not as important as internal urethral sphincter d. Clean intermittent catheterization e. Chronic catheters (urethral or cystostomy) f. *Urethral stents ii. Decreased outlet resistance (urethral incompetence) 1. Neurogenic or myogenic 2. Most common cause is urethral sphincter mechanism incompetency in female dogs a. Uncommon in male dogs or cats and male dogs b. In these animals, search for other causes 3. Animal “leaks” urine 4. Treatment: STIMULATE urethra a. Alpha agonists – phenylpropanolamine, pseudoephedrine i. Continence in 85-90% 686

ii. Once a day treatment may be as effective as three times a day administration with fewer side effects b. Reproductive hormones i. Estrogens 1. Increase alpha adrenergic receptor responsiveness and improve urethral vascularity and other mucosal characteristics 2. Usually given as loading dose and then lowest maintenance dose 3. Safe and reasonably effective (40-65%0 4. Estriol (Incurin) is the only approved estrogen for use in dogs and is reported to have a 93% excellent response rate ii. GnRH analogs 1. Chronically unsuppressed FSH and LH release (due to lack of negative feedback) in ovariectomized dogs may contribute to urinary incontinence 2. Administration of GnRH analogs paradoxically reduce FSH and LH over time 3. Was found effective in 12/13 dogs in one study and in another study 9/23 dogs were continent from 70-575 days with another 10/23 having partial response; however, the 23 dogs also responded to PPA c. Urethral bulking i. Involves injection of an agent submucosally in the proximal urethra via cystoscopy 1. Thought to create artificial urethral cushions improving urethral closure (coaptation) 2. Also functions as central filler volume increasing length of smooth muscle fibers and closure power of internal urethral sphincter 3. There are no bulking agents available for use in veterinary medicine. Historically, glutaraldehyde cross-linked collagen was used, but has been withdrawn from market. A study with polydimethylsiloxane has promising results. d. Artificial sphincters/urethral occluding devices i. A urethral occluding device is similar to a blood pressure or vascular cuff ii. It is placed surgically around proximal urethra with a loose fit iii. A tube connects the device with a subcutaneously implanted injection port, which provides a means to increase pressure within the device and therefore urethral pressure in area of internal urethral sphincter iv. Continence rates are high; however, they may require adjustment with time v. Urethral obstruction and irritation with clinical signs may occur e. Surgical techniques: slings, plication, culposuspension iii. Reflex dyssynergia 1. Incoordination between bladder contraction and urethral relaxation 2. Animal usually postures normally, initiates a good stream, but stream stops yet animal continues to posture and attempt to void a. Treatment involves relaxing urethra b. If bladder does not completely empty despite urethral relaxation, then add bladder stimulant iv. Paradoxical incontinence 1. Outflow obstruction resulting in bladder overdistention 2. Increased bladder pressure results in “leaking” of urine through or around obstruction 3. Animal dribbles urine with a full bladder and is unable to void 4. May be due to functional or mechanical outflow obstruction and is often associated with bladder atony

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Table. Drugs used to manage dogs and cats with micturition disorders. Agent Mechanism of action Recommended dosage Adverse effects Agents used to increase urinary bladder contractility Bethanechol Parasympathomimetic; direct D: 5-25 mg PO q8h Nausea, vomiting, cholinergic activity C: 1.25-7.5 mg PO q8h salivation Metoclopramide Prokinetic; sensitizes to D, C: 0.2-0.5 mg/kg PO q8h Behavior changes acetylcholine Agents used to decrease urinary bladder contractility Propantheline Parasympatholytic; acetylcholine D: 7.5-30 mg PO q8h Nausea, vomiting, blockade C: 5-7.5 mg PO q8h or 7.5 mg PO constipation, sedation, q72h increased ocular pressure Oxybutynin Parasympatholytic; antispasmodic; D: 1.25-5 mg PO q8-12h Nausea, vomiting, urine detrusor relaxation C: 0.5-1.25 mg PO q8-12h retention, diarrhea, sedation Flavoxate Direct smooth-muscle relaxant D: 100-200 mg PO q6-8h Weakness Dicyclomine Anti-muscarinic D: 10 mg PO q6-8h Nausea, vomiting, constipation, sedation, increased ocular pressure Imipramine Tricyclic antidepressant with D: 5-15 mg PO q12h Seizures, tremors, anticholinergic, alpha-and beta- C: 2.5-5 mg PO q12h tachycardia, agonist effects, detrusor smooth hyperexcitability muscle relaxation and urethral muscle contraction Amitriptyline Tricyclic anti-depressant D: 2.2-4.4 mg/kg PO q12h Sedation, anticholinergic C: 0.5-1 mg/kg PO q24h effects Agents used to increase urethral resistance Estriol (Incurin) Reproductive hormone D: 0.5-2 mg PO q24h initially; followed by 0.5-2 mg PO q2-3d DES Reproductive hormone D (females): 0.1-1 mg PO q24h for 5 Signs of estrus, bone days (approximately 0.2 mg/kg) marrow suppression followed by 0.1-1 mg PO q7d Premarin Reproductive hormone D: 20 mcg/kg q24hr x 7-10d; then q1- 3d Testosterone Reproductive hormone D (males): 2.2 mg/kg SQ or IM q2-3d Aggression, prostatic propionate C (males): 5-10 mg IM as needed disease, perineal hernia Testosterone cypionate D (males): 2.2 mg/kg IM q30d or 200 mg IM q30 d Phenylpropanolamine Alpha agonist; urethral smooth D: 12.5-50 mg PO q8h; 1-2 mg/kg PO Anxiety, cardiac muscle contraction q8h arrhythmias, anorexia, C: 1.0-1.5 mg/kg PO q8h hypertension Ephedrine Alpha agonist; urethral smooth D: 1.2 mg/kg PO q8h or 5-15 mg PO Anxiety, cardiac muscle contraction q8h arrhythmias, C: 2-4 mg/kg PO q6-12h or 2-4 mg hypertension PO q8h Agents used to decrease urethral resistance Phenoxybenzamine Alpha antagonist; urethral smooth D: 5-15 mg PO q12h Hypotension, muscle relaxation C: 2.5-10 mg PO q24h tachycardia, vomiting, D, C: 0.25 mg/kg PO q12h diarrhea, increased intraocular pressure

Prazosin Alpha antagonist; urethral smooth D: 1 mg/15kg PO q12-24hr Hypotension muscle relaxation C: 0.25-0.5 mg PO q12-24h Tamsulocin Alpha antagonist, urethral smooth D: 0.03-0.2 mg/10kg q24h Hypotension muscle relaxation Doxazosin Alpha antagonist, urethral smooth D: 0.1-1.0 mg/kg PO q24h Hypotension muscle relaxation Terazosin Alpha antagonist; urethral smooth D, C: 0.5-5 mg PO q12-24hr Hypotension muscle relaxation 688

Terazosin Alpha antagonist, urethral smooth D: 0.1-1.0 mg/kg PO q24h Hypotension muscle relaxation Fiduxosin Alpha antagonist, urethral smooth D: 0.1-3.0 mg/kg PO q24h Hypotension muscle relaxation Diazepam Striated muscle relaxation; central D: 0.2 mg/kg PO q8h or 2-10 mg PO Sedation, paradoxical nervous system depressive q8h excitement effect C: 2.5-5 mg PO q8h or as needed or 0.5 mg/kg IV Dantrolene Striated muscle relaxation; direct D: 3-15 mg/kg PO q24h divided or Weakness, action 0.5-1 mg/kg PO q8h hepatotoxicity C: 0.5-1 mg/kg PO q12h Acepromazine Urethral muscle relaxation by D: 0.1-2 mg/kg PO q8-12h Sedation, hypotension, neuroleptic effect; alpha C: 0.1 mg/kg IV or 1.1-2.2 mg/kg PO seizures antagonism q12h Aminopromazine Smooth muscle relaxation D, C: 2.2 mg/kg PO q12h

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Urine a Losing Situation: Proteinuria Joe Bartges, DVM, PhD, DACVIM, DACVN Cornell University Veterinary Specialists Stamford, CT

Key clinical diagnostic points  Glomerulus represents a barrier and functions to filter plasma  Components include  Fenestrated endothelium of glomerular capillary  Glomerular basement membrane  Podocytes containing negatively-charged slit diaphragms  Filtration is limited to molecules that are >68,000 Daltons  Function  Size and charge determine the “filterability” of a substance from plasma into Bowman’s space  Size limit is 68,000 to 70,000 Daltons  Albumin is 65,000, but its negative charge precludes filtration  From Bowman’s space, the filtrate continues through the tubules  For solutes to pass freely through the glomerulus, filtration of a solute is a function of GFR and plasma concentration of the solute:  GFR = Kf X net filtration pressure  Kf is the permeability coefficient, which is a function of surface area and permeability  Net filtration pressure is the sum of Starling’s forces (hydrostatic and oncotic) between plasma and Bowman’s space  Hydrostatic pressure in glomerular capillaries has greatest influence on GFR – it is about 60 mmHg  Net filtration pressure is typically about 10 mmHg  Diagnosis  Finding of proteinuria should be interpreted in light of other findings on urinalysis  Always examine urine sediment to rule-out inflammation, infection, or hemorrhage, which is associated with proteinuria  Proteinuria with an inactive sediment may indicate glomerular disease  Qualitative methods  Dipstick pad . Part of most (perhaps all) urine dipsticks . Colorimetric method . Amino groups of proteins bind to an indicator in filter paper producing a color change . Change is graded subjectively to a standard . Most sensitive to presence of albumin . Range: 30-3,000 mg/dl  Graded as negative, trace, and 1+ to 4+ depending on intensity of color change . Recent studies suggest this analytical pad is not very good – many false positives and false negatives – and additional testing for proteinuria should be performed when there is a concern . False positives  Alkaline urine pH (> 7.5)  Contamination of urine with quaternary ammonia compounds (eg some cleaners and disinfectants)  Prolonged contact with urine  Any pigment in urine may absorb into the pad . False negatives  Very dilute urine  Very acidic urine  Presence of some abnormal proteins (eg Bence Jones proteins (myeloma proteins)) o Sulfosalicylic acid . 3-5% sulfosalicylic acid solution is mixed with an equal volume of urine . Turbidity that results from acid precipitation of protein is evaluated . Good for albumin and Bence Jones proteins . Range: 5-5,000 mg/dl . False positive  Radiocontrast agents  Certain drugs (eg penicillin, cephalothin, sulfonamide, thymol) 690

. False negative  Very alkaline urine  Very dilute urine  Quantitative methods . Microalbuminuria  Recently, an “early diagnosis of renal disease” (ERD) test has become available o Measures micro-albuminuria – range of 1 to 30 mg/dl o Less than detectable by dipstick o May be useful in detecting early renal disease . 19% of healthy dogs have micro-albuminuria . 36% of dogs seeking veterinary care have micro-albuminuria . True with congenital or induced glomerular disease . No data (yet) concerning spontaneously occurring non-glomerular renal disease . Used in human beings for detection of early renal disease due to diabetes mellitus and hypertension (small capillary (glomerular) damage) . Despite inherent issues, there are indications for determining microalbuminuria including  Not overtly proteinuric, but clinical disease likely to be associated with proteinuria  Not overtly proteinuric, middle-aged or older  When conventional tests for proteinuria are equivocal or conflict  Dogs and cats known to be at risk for developing a glomerulopathy . Verification of significant proteinuria  Evaluate urine dipstick in light of urine sediment examination (eg “clean” or “dirty” sediment)  As little as 10% whole blood (volume/volume) can result in a positive dipstick reaction  Inflammation can result in proteinuria even without hematuria  If proteinuria is present with a “quiet” sediment and in a dilute urine, consider doing a urine culture  A urinary tract infection can result in very large amounts of protein in urine due to exudation  Also, evaluate in light of urine specific gravity and urine pH  A “trace” amount of protein in a concentrated urine is probably less significant or even an artifact than if it occurs in very dilute urine  Likewise, a “trace” amount of protein in a very alkaline urine pH could be an artifact due to the alkalinity of the sample  If proteinuria is present with a “clean” sediment and a bacterial urinary tract infection has been ruled-out, then the degree of proteinuria should be verified and quantitated  Urine protein-to-urine creatinine ratio (UPC)  A spot urine sample can be collected by any method (as long as hemorrhage is not induced)  Creatinine concentration (mg/dl) and protein concentration (mg/dl) is determined  The result is a unit-less number  Normal UPC in dogs is <0.5:1.0 and cats < 0.4:1.0  Suspect UPC is 0.4/0.5:1.0 to 1.0:1.0  Significant proteinuria occurs when UP:UC is > 1.0:1.0 o With CKD . Relative risk of mortality is 3 times higher when UPC > 1 . Risk of adverse outcome increased by 1.5-fold for every 1 unit increment of UPC above 1  How is proteinuria investigated?  Make sure not artifact o False positives: pigment, alkaluria  Voided sample? o If yes – then check cystocentesis (r/o extra-urinary)  Evaluate plasma proteins and color o r/o pre-renal (e.g. hyperglobulinemia, hemolysis, etc)  Evaluate urine sediment o * * * Active vs inactive sediment (post-renal) * * * . If active and signs of upper tract dz -> nephritis . If inactive -> evaluate further (renal)  Renal o If minimal: re-evaluate in 2 weeks (functional ?) o Persistent -> UPC . UPC < 2: glomerular or tubular . UPC > 2: glomerular

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What is the clinical significance of renal proteinuria?  Proteinuria ≠ renal proteinuria  Pre-renal  Physiologic proteinuria (exercise, stress, fever, seizures, venous congestion, etc)  Overload proteinuria (hyperproteinemia, myoglobinemia, and hemoglobinemia)  Post-renal – Most common cause  Inflammation  Infection  Hemorrhage  When renal proteinuria = renal disease  Will the kidney disease lead to morbidity or mortality  Is the kidney disease a sign of some underlying condition  Is therapy indicated to prevent additional renal or systemic injury  Types  Glomerular  Tubular  Interstitial

Renal biopsy  Indications  Renal biopsy is most useful with  Nephrotic syndrome/glomerular disease  Mass lesions/neoplasia  Acute renal failure (for diagnosis and prognosis)  Patients with proteinuria  Cats with feline infectious peritonitis (diagnosis)  Suspected familial or congenital renal disease  Perinephric cysts (fine needle aspiration only)  Investigation  Renal biopsy may be useful with  Infectious renal disease (fine needle aspiration of tissue or pelvic urine)  Culture of pelvic urine  Slowly progressive tubulointerstitial disease  Patients with undiagnosed renal hematuria  Renal biopsy is not helpful or should not be performed with  Chronic renal failure (unless associated with neoplasia)  Polycystic kidney disease  When performing a renal biopsy, the core of tissue is divided for histopathology (light microscopy = LM), immunofluorescence (IF), and electron microscopy (EM) Conservative approach  Serially monitor urinalysis, UPC, and renal function  Patients with stable or improving mild proteinuria (UPC < 2)  If severe or progressive proteinuria – investigate further  Identify and treat inciting disorder  Limit proteinuria  Limits albumin loss and consequences of hypoalbuminemia  Renoprotective  Proteinuria is nephrotoxic  Activates fibrosis and inflammatory pathways

General clinical signs of glomerular disease  Vary with severity of disease and underlying cause, if any  Azotemia may or may not be present and is unassociated with the degree of proteinuria and hypoalbuminemia  Mild to moderate proteinuria results in serum albumin concentrations >1.5 g/dl, but < 2.5-3.0 g/dl o At this level, clinical signs often include polyuria, weight loss, and lethargy o With severe or heavy proteinuria, serum albumin is < 1.5 g/dl, and clinical signs are more severe  In addition to aforementioned signs o Muscle wasting

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o Edema/ascites o Nephrotic syndrome . Occurs with severe proteinuria and is characterized by proteinuria, marked hypoalbuminemia, hypercholesterolemia, hyperlipidemia, and edema

Therapy  Treatment is often frustrating and biologic course is variable  Goals of therapy are similar to those for CKD with additional goal of increasing serum albumin concentration and minimizing likelihood of nephrotic syndrome  Treatment includes: Treat the underlying cause, if it can be identified  Two major glomerulopathies  Glomerulonephritis  Glomerulonephritis (GN) is better termed glomerulopathy  “-itis” implies inflammation, which typically occurs, but is not always present depending on cause of the glomerular disease (eg congenital renal disease, glomerulosclerosis)  Many causes that have been described, primarily in dogs: Familial Doberman pinscher, Samoyeds (X-linked dominant), Bull terrier (autosomal dominant), soft-coated Wheaton Terrier, Greyhound, Burmese mountain dog, Rottweiler, English Cocker spaniel (autosomal dominant), Norwegian Elkhound, Brittany spaniel (autosomal dominant), Deficiency of C3 results in recurrent bacterial urinary tract infections and membranoproliferative GN Neoplastic Lymphosarcoma, mastocytosis, hemangiosarcoma, adenocarcinoma Infectious Bacterial endocarditis, infectious canine hepatitis, brucellosis, dirofilariasis, ehrlichiosis, systemic fungal or bacterial infection, feline infectious peritonitis, feline leukemia virus Inflammatory Systemic lupus erythematosus, chronic pancreatitis, chronic pyoderma, chronic otitis externa, polyarthritis Miscellaneous Hyperadrenocorticism, diabetes mellitus, chronic glucocorticoid treatment, systemic arterial hypertension, idiopathic  Any process resulting in antigenic stimulation may result in GN  In most cases, underlying cause(s) is/are not identified; therefore, most are classified as idiopathic  Glomerulopathies may be immune-mediated or non-immune-mediated:  Immune-mediated GN:  Accounts for @ 48% of renal proteinuria in dogs; amount in cats…?  Etiopathogenesis is related to presence of immune complexes in glomerular capillary walls  Histologically, GN can be classified as: . Proliferative:  Mesangial and epithelial cell proliferation and infiltration (primarily neutrophils)  Cellular proliferation compresses glomerular capillaries resulting in decreased blood flow and GFR . Membranous:  Thickening of basement membrane due to subepithelial deposition of immune complexes  Membranoproliferative: o Combination of membranous and proliferative GN  Immunofluorescence can be used to document the immune-mediated nature; however, few labs do this technique and even fewer do it well . Prognosis is thought to be related to histologic type with membranous having a better prognosis than proliferative or membranoproliferative.  Non-immune-mediated: . Glomerular disease may occur due to developmental abnormalities in glomerular structure and function . Glomerular disease (sclerosis characterized by glomerular thickening and mesangial expansion) has been reported to occur with:  Glucocorticoid excess (endogenous or exogenous)  Systemic arterial hypertension  Diabetes mellitus  Renal failure  Immunofluorescence studies would be negative 693

 Amyloidosis . Amyloid is a beta-pleated sheet of serum amyloid A protein . Deposits in and around glomerulus, usually beginning in the tubulointerstial area . Amyloidosis is uniformly progressive in nature and animals invariably develop chronic renal failure . It may occur:  Primary familial disease o Primarily described in Shar pei dogs Abyssinian cats o In these animals, amyloid may be deposited primarily in the medulla and not glomerulus o Proteinuria, therefore, may not be present o Amyloidosis develops typically in animals under 5-6 years of age o Shar pei dogs with amyloidosis often develop an arthropathy associated with fever and joint pain (called Shar pei fever, Shar pei swollen hock syndrome, Mediterranean Fever) o Has also been described in Siamese cats, Oriental shorthair cats, Walker hound dogs, Beagle dogs, and Collies  Secondary to chronic inflammatory diseases (eg infections, inflammatory organ disease, or cancer) . Clinical signs of amyloidosis include:  Proteinuria  Edema (depending on degree of proteinuria and hypoalbuminemia)  Chronic renal failure  Systemic arterial hypertension (and its related clinical signs – see Chronic Renal Failure lectures)  Inappetence and weight loss  Fever (depending on cause)  Arthropathy (depending on cause) – especially in Shar Pei breed  Other signs related to inciting cause of secondary amyloidosis . Diagnosis:  Differentiated from other glomerulopathies by renal biopsy  On light microscopy, amyloid appears as an eosinophilic substance in the mesangium and/or interstitium  Congo red stain using polarized light confirms the presence of amyloid (Congo red gives an “apple green” color when viewed under polarized light)  Amyloid may occur outside of the glomeruli particularly in the medulla in cats; therefore, it may be missed with a renal cortical biopsy Feed a protein-restricted diet  Studies have shown that dietary protein restriction decreases the degree of proteinuria and increases serum creatinine concentration. Supplementing dietary protein actually makes the situation worse.  Decrease sodium intake. This can usually be accomplished by feeding a low protein, renal failure diet. Dietary salt restriction aids in decreasing fluid retention. Administer an angiotensin-converting enzyme inhibitor  Enalapril is the only ACE inhibitor that has been evaluated in dogs with proteinuria although other ACE inhibitors have been evaluated in dogs with induced diabetes mellitus (lisinopril) and in human beings (captopril, ramipril, etc). Benazepril has been shown to reduce proteinuria in cats. Benazepril is excreted more through biliary system than urinary system (although it is renally excreted as well) when compared with enalapril; therefore, it may be safer to use in animals with renal azotemia.  Enalapril has been shown in a controlled study to decrease proteinuria, increase serum albumin concentration, and prolong survival in dogs with GN Enalapril in dogs or benazepril may be tried  There is a potential to worsen azotemia if present; therefore, start with a lower dose in azotemic animals and monitor BUN and creatinine  Indicated when UPC is > 1-2 in IRIS stage 1 or > 0.4 (cats) and 0.5 (dogs) in IRIS stage 2-4  Initial dose: 0.25 mg/kg PO q12h Administer anti-inflammatory drugs to decrease platelet aggregation  Platelet activation and intraglomerular thrombosis occurs with glomerular disease  Aspirin is usually administered at 0.25-0.5 mg/kg PO q12-24hr in dogs or ½-1 baby aspirin q3d in cats.  Efficacy is not proven in dogs, but it is in human beings.

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Consider omega-3 fatty acids  Theoretically, diets containing higher levels of omega-3 fatty acids may decrease inflammation. The omega-3 fatty acid becomes incorporated into plasma lipid membranes instead of arachidonic acid. The prostaglandins, thromboxanes, and leukotrienes produced from metabolism of omega-3 fatty acids tend to promote less inflammation and coagulation.  In a chronic CKD model, dogs consuming a diet with an omega-6-to-omega-3 fatty acid ratio of 5:1 maintained GFR longer, survived longer, and had less inflammatory prostaglandin excretion than when dogs consumed diets containing higher levels of omega-6 fatty acids. There is no data in dogs with proteinuria. Furthermore, cats with chronic renal failure do not appear to respond to omega-3 fatty acid supplementation.  Most renal failure diets contain an omega-6-to-omega-3 fatty acid ratio of 5:1. Supplementation of omega-3 fatty acid should be done to achieve a ratio of omega-6-to-omega-3 fatty acids of somewhere between 1:1 to 5:1. Therefore, the amount of omega-3 fatty acid supplementation must be done based on the fat content of the diet and type of fat in the diet  Omega-3 fatty acids can be supplemented with diet with a starting dose of 300 mg of EPA + DHA per 10 lbs per day. Remember, EPA is the 20-carbon long-chain fatty acid and DHA is the 22-carbon long-chain fatty acid. Consider immunosuppressive drugs  Administration of immunosuppressive drugs to dogs with proteinuria is controversial. None have been shown to be effective in controlled studies, although there are sporadic case reports of response. However, biopsies show that 48.7% of glomerular disease in dogs have an immune-mediated basis  In human beings, glucocorticoids are often administered. Studies in dogs have shown that in most cases of proteinuria, glucocorticoid administration is not beneficial and is often associated with a worsening of the proteinuria. Glucocorticoids appear to promote glomerulosclerosis and intraglomerular hypertension. Therefore, glucocorticoids are not recommended unless the proteinuria is secondary to glucocorticoid-responsive systemic disease.  Cyclosporine was not found to be effective in dogs with idiopathic GN in a controlled, blinded study. Therefore, it cannot be recommended at this time.  Other immunosuppressive drugs that may show benefit, but that have not been evaluated in placebo-controlled, blinded studies are azathioprine (2 mg/kg PO q24h x 2 weeks, then 1 mg/kg PO q24h, then 1 mg/kg PO q48h), cyclophosphamide (50 mg/m2 PO q48h), and chlorambucil (2-6 mg/m2 PO q24-48h). The most promising are mycophenolate (D: 20 mg/kg PO q12h for 3-4 weeks, then 10 mg/kg PO q12h; C: 10 mg/kg PO q12h) and azathioprine + chlorambucil  Most immunosuppressive drugs are also cytotoxic; therefore, their administration may be associated with worsening azotemia.  The decision to use immunosuppressive therapy should be based on the likelihood of an immune-mediated cause of proteinuria, the patient’s overall condition, and the ability to monitor the patient. Consider diuretics to decrease sodium retention and edema/ascites  In human beings with nephrotic syndrome, diuretics are often used to decrease ascites/edema. Commonly a combination of a loop diuretic (such as furosemide) and a thiazide diuretic (such as chlorothiazide) are used. These diuretics promote natriuresis thereby decreasing sodium and fluid retention.  Furosemide is often used in veterinary medicine to decrease fluid retention and should be considered in dogs or cats that have nephrotic syndrome. Combination diuretic therapy may be considered in animals that are refractory to single agent therapy.

Treatment targets  Ideal goal: reduce UPC to < 0.5 in dogs and 0.4 in cats  Realistic goal: reduce UPC by at least 50%

Additional therapies  If goal is not achieved: o Increase dosage of ACE-I and monitor o Angiotensin receptor blocking (ARB) agent . Some ATII escapes ACE inhibition . ARB block ATII interaction at receptor . Same tendency for complications as with ACE-I . I typically use Losartan (1 mg/kg PO q12h); however, irbesartan has been evaluated in dogs (5 mg/kg PO q12-24h) o Immunosuppression, if not done o Doxycycline

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. Loose information of decreasing proteinuria in humans . Metalloproteinase inhibitor – anti-inflammatory . Used with tick-borne disease-associated glomerular disease

Prognosis  Generally poor  Most patients dead within 1-2 months of diagnosis  However, can be stable for long time and may resolve with therapy

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Getting the Most out of Liquid God: Urinalysis Joe Bartges, DVM, PhD, DACVIM, DACVN Cornell University Veterinary Specialists Stamford, CT

Urinalysis is an important laboratory test that can be readily performed in veterinary practice, and is considered part of a minimum database. Collected urine should be evaluated within 30 min. It may be refrigerated for up to 24 hours or submitted to an outside diagnostic laboratory; however, this may alter results.

Urine appearance Color Urine is typically transparent and yellow or amber. The intensity of color is in part related to the volume of urine collected and concentration of urine produced; therefore, it should be interpreted in context of urine specific gravity (USG). Significant disease may exist when urine is normal in color. Abnormal urine color may be caused by presence of endogenous or exogenous pigments, but it does not provide specific information. Interpretation of semi-quantitative, colorimetric reagent strips may yield false-positive results because of pigmenturia. Clarity Urine is typically clear. Odor Normal urine has a slight odor of ammonia; however, the odor is dependent on urine concentration. Some species, such as cats, have pungent urine odor because of urine composition. Bacterial infection may result in a strong odor due to pyuria; a strong ammonia odor may occur if the bacteria produce urease.

Urine chemistries Semi-quantitative, colorimetric, chemical test pads are usually done prior to centrifugation; however, if urine is discolored or turbid, it may be beneficial to perform these tests on supernatant. Specific gravity The USG is determined using a refractometer designed for veterinary samples, which includes a scale calibrated specifically for cat urine. In healthy animals, USG is highly variable, depending on fluid and electrolyte balance. Interpretation of USG depends on clinical presentation and serum chemistry findings. An animal that has prerenal azotemia will have hypersthenuric urine with USG >1.025-1.080. Dilute urine in an azotemic animal is abnormal. Semiquantitative, colorimetric reagent strips Reagent strips can be used to perform semi-quantitative chemical evaluations. They determine urine pH, protein, glucose, ketones, bilirubin/urobilinogen, and occult blood. Some reagent strips include test pads for leukocyte esterase (for detection of WBC), nitrite (for detection of bacteria), and USG; these are not valid in animals and should not be used. Reagent strips are adversely affected by moisture and have a limited shelf life. Urine pH Urine pH is typically acidic in dogs and cats, but varies depending on diet, medications, or presence of disease. Reagent strip colorimetric test pads for pH determination are accurate to within ± 0.5 pH units. Urine pH will affect crystalluria. Protein The protein test pad uses a color indicator (tetrabromophenol blue), which detects primarily albumin in urine. Results range from 30 mg/dL to 3,000 mg/dL). A positive reaction must be interpreted in light of USG, pH, and urine sediment examination. Proteinuria can be measured using sulfosalicylic acid precipitation, which detects albumin and globulins; however, it is not accurate. If proteinuria is present with inactive urine sediment, its significance can be verified and quantitated by dividing the urine protein concentration by the urine creatinine concentration (urine protein to urine creatinine ratio; UPC). A semi-quantitative microalbuminuria test is available to detect urinary albumin in the range of 1 to 30 mg/dL. It uses ELISA technology specific for canine or feline albumin. Glucose Glucose is detected by a glucose oxidase enzymatic reaction that is specific for glucose. Glucosuria is not present normally because the renal threshold for glucose is >180 mg/dL in most species and >240 mg/dL in cats. With euglycemia, the amount of filtered glucose is less than the renal threshold and all of the filtered glucose is reabsorbed in the proximal renal tubules. If glucosuria is present, blood glucose concentration should be determined. Ketones Ketones are produced from fatty acid metabolism, and include acetoacetic acid, acetone, and -hydroxybutyrate. The ketone test pad detects acetone and acetoacetic acid, but not -hydroxybutyrate.

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Bilirubin/urobilinogen When hemoglobin is degraded, the heme portion is converted to bilirubin, which is conjugated in the liver and excreted in bile. Some conjugated bilirubin is filtered by the glomerulus and excreted in urine. Male dogs have a higher secretory ability compared with female dogs; bilirubinuria in cats is always abnormal. In dogs with concentrated urine, a small amount of bilirubin can be normal. Urobilinogen, formed from bilirubin by intestinal microflora, is absorbed into the portal circulation and is excreted renally. The test is not clinically useful. Occult blood The occult blood test pad uses a “pseudoperoxidase” method to detect intact RBC, hemoglobin, and myoglobin. A positive result should be interpreted with microscopic examination of urine sediment.

Urine sediment Microscopic examination of urine sediment should be part of a routine urinalysis. For centrifugation, 3-5 mL of urine is transferred to a conical centrifuge tube. Urine is centrifuged at 1,000-1,500 rpm for 5 minutes. The supernatant is decanted, leaving 0.5 mL of urine and sediment in the tip of the conical tube. The sediment is resuspended by tapping the tip of the conical tube against the table several times. A few drops of the sediment are transferred to a glass slide, and a cover slip is applied. Examination of unstained urine is recommended for routine samples. Microscopic examination is performed at 100X (for crystals, casts, and cells) and 400X (for cells and bacteria) magnifications. Contrast of the sample is enhanced by closing the iris diaphragm and lowering the condenser of the microscope. Stains can be used to aid in cell identification but may dilute the specimen and introduce artifacts such as stain precipitate and crystals. Use of a modified Wright’s stain increases the sensitivity, specificity, and positive and negative predictive values for detection of bacteria. Red blood cells RBC’s are small, round, have orange tint, and smooth appearance. Normal urine should contain <5 RBC/field at 400X magnification. White blood cells WBC’s are slightly larger than RBC and have grainy cytoplasm. Normal urine should contain <5 WBC/field at 400X magnification. Epithelial cells Transitional epithelial cells resemble WBC but are larger. They have a greater amount of grainy cytoplasm and a round, centrally located nucleus. Occasionally, neoplastic transitional cells may be observed in an animals. Cylindruria (casts) Casts are elongated, cylindrical structures formed by mucoprotein congealing within renal tubules. Hyaline casts are mucoprotein precipitates, transparent, and have parallel sides and rounded ends. Epithelial cellular casts form from entrapment of sloughed tubular epithelial cells in the mucoprotein. Granular casts are thought to represent degenerated epithelial cellular casts. Waxy casts have a granular appearance. They typically have sharp borders with broken ends. Other cellular casts include erythrocyte casts and WBC casts, and are always abnormal. Fatty casts are not common, but can be observed with disorders of lipid metabolism. A few hyaline or granular casts are considered normal; however, presence of cellular casts or other casts in high numbers indicates renal damage. Infectious organisms Presence of bacteria in urine collected by cystocentesis indicates infection. Small numbers of bacteria from the lower urogenital tract may contaminate voided samples or samples collected by catheterization and do not indicate infection. Bacterial rods are most easily identified. Particles of debris may be mistaken for bacteria. Suspected bacteria can be confirmed by staining urine sediment with modified Wright’s stain; however, aerobic culture is best for confirmation. Rarely, yeast and fungal hyphae and parasitic ova may be observed in urine sediment. Their presence is not always associated with clinical disease. Crystals Many urine sediments contain crystals. The type of crystal present depends on urine pH, concentration of crystallogenic materials, urine temperature, and length of time between urine collection and examination. Crystalluria is not synonymous with urolithiasis and is not necessarily pathologic; uroliths may form without observed crystalluria. Struvite crystals appear typically as “coffin-lids” or “prisms”; however, they may be amorphous. Struvite crystalluria in dogs is not a problem unless there is a concurrent bacterial urinary tract infection with a urease-producing microbe. Cats do form struvite uroliths without a bacterial urinary tract infection. Calcium oxalate dihydrate crystals appear as squares with an “X” in the middle or “envelope-shaped.” Calcium oxalate monohydrate crystals are “dumb-bell” shaped. Calcium oxalate crystalluria occurs less commonly in dogs and cats; if persistent, it may indicate an increased risk for calcium oxalate urolith formation. Ammonium acid urate crystals suggest liver disease (eg, portosystemic shunt). These crystals occur in acidic urine and are yellow-brown spheres with irregular, spiny projections; however, they may also be amorphous. Certain breeds of dogs, e.g. Dalmatians, can normally have ammonium acid urate crystalluria. Cystine crystals are 6-sided and of variable size. They occur in acidic urine. Presence of cystine crystals represents a proximal tubular defect in amino acid reabsorption. Bilirubin crystals occur with bilirubinuria; however, they may be normal in dogs.– Lipid, spermatozoa, and plant material may occasionally be seen.

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Bladder tumor antigen test (VBTA) The VBTA can be used as a screening test for transitional cell carcinoma in dogs. The results are not specific and non-neoplastic disease (e.g. urinary tract infections, hematuria, etc) can give positive results. A negative test; however, is meaningful in that a transitional cell carcinoma is not likely to be present. This test may be useful for routine screening of dogs at higher risk of developing transitional cell carcinoma (e.g. Scottish terriers) that do not have other signs or laboratory findings of lower urinary tract disease.

Point-of-care testing for urinary tract infections There are several point-of-care tests for evaluating a patient for a urinary tract infection. They suffer from either a low level of sensitivity or specificity or both. As mentioned before, staining the urine sediment with a modified Wright’s stain is effective in determining whether a urinary tract infection is present or not, but urine culture is still the most reliable if performed correctly.

References Bartges, J. W. "Discolored Urine." In Textbook of Small Animal Internal Medicine, edited by S. J. Ettinger and E. C. Feldman, 112-114. Philadelphia: WBSaunders, 2005. Olin, S. J., J. W. Bartges, R. D. Jones and D. A. Bemis. "Diagnostic Accuracy of a Point-of-Care Urine Bacteriologic Culture Test in Dogs." J Am Vet Med Assoc 243, no. 12 (2013): 1719-25. Osborne, C. A., J. B. Stevens, J. P. Lulich, L. K. Ulrich, K. A. Bird, L. A. Koehler and L. L. Swanson. "A Clinician's Analysis of Urinalysis." In Canine and Feline Nephrology and Urology, edited by C. A. Osborne and D. R. Finco, 136-205. Baltimore: Williams & Wilkins, 1995. Swenson, C. L., A. M. Boisvert, J. M. Kruger and S. N. Gibbons-Burgener. "Evaluation of Modified Wright-Staining of Urine Sediment as a Method for Accurate Detection of Bacteriuria in Dogs." J Am Vet Med Assoc 224, no. 8 (2004): 1282-9.

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Urine a Quandary: Feline Idiopathic Cystitis Joe Bartges, DVM, PhD, DACVIM, DACVN Cornell University Veterinary Specialists Stamford, CT

Prevalence of lower urinary tract disease is more common in cats between 1 and 10 years of age; whereas in dogs, the prevalence increases with advancing age 12 Dogs Figure. Prevalence of lower urinary tract disease in dogs 10 Cats (1980-1995) and cats (1980-1990) reported through the Veterinary Medical Database 8  In cats >10 years of age, bacterial urinary tract 6 infection is most common 4

 In young cats, idiopathic lower urinary tract disease Morbidity

occurs most commonly Proportional 2 0

0 to 1 1 to 2 2 to 4 Age4 to (years) 7 7 to 10 10 to 15 > 15 Figure. Causes of lower urinary tract disease in cats from 3 studies.

60 Kruger 1991 50 Buffington 1997 Bartges 1996 40 30 %20 10 0

What is feline idiopathic cystitis (idiopathic feline lower urinary tract disease)? Currently, there are 2 hypotheses concerning FIC Viral hypothesis  A gamma-herpesvirus, a calicivirus, and a retrovirus have been isolated from urine and tissues from cats with naturally occurring idiopathic lower urinary tract disease  Reproducible clinical evidence that viruses cause naturally occurring disease is scarce  Viral particles have been observed in plugs recovered from cats with matrix-crystalline urethral plugs Neurogenic inflammation hypothesis  Similar in some respects to hypothesis for interstitial cystitis in women  Cats with idiopathic lower urinary tract disease have decreased urinary glycosaminoglycan concentration and similar light microscopic changes to interstitial cystitis  This may represent a central nervous system problem o In cats with FIC, there appears to be a dysregulation of the sympathetic nervous system o sANS activation w/o activation of hypothalamic-pituitary-adrenal axis for counter-regulation . CRF release w/o appropriate  cortisol (adrenocortical hypoplasia) . tissue inflammatory response . epithelial permeability  Fluorescein studies . neuron firing ->pain (nitric oxide?) . “flare-ups” of signs with stress o Developmental disorder (Pandora Syndrome) . Early age adverse experience (?)  Queen stress -> cortisol suppression of adrenal development in kittens

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. Other organ system problems Clinical signs of feline lower urinary tract disease  Causes of lower urinary tract disease in cats present with similar clinical signs including, but not limited to: o Pollakiuria o Hematuria o Stranguria o Dysuria o Inappropriate urination o +/- Urethral obstruction

Diagnostic testing for cats with lower urinary tract signs  CBC and biochemical analysis are normal unless urethral obstruction is present  Urinalysis reveals hematuria o Pyuria and possibly bacteriuria present, if UTI o Crystalluria may be present with plugs or stones  Urine culture is negative unless a UTI is present  Abdominal radiography and ultrasonography may be normal o A large bladder may be found with urethral obstruction o Uroliths may be observed or “sand” o Urinary bladder wall may be thickened on ultrasound  Cystoscopically, small pin-point hemorrhages (glomerulations) are found and occasionally larger mucosal ulceration o These can be found with other diseases of the lower urinary tract  Bladder biopsy often reveals submucosal edema, mucosal ulceration, possible submucosal inflammation, possible fibrosis o May be observed with other diseases of the lower urinary tract o We routinely biopsy the bladder wall for histopathologic examination and aerobic and anaerobic bacterial culture  Idiopathic disease is a diagnosis of exclusion

Treatment of lower urinary tract disease Urethral obstruction  Obstruction may occur from uroliths or from matrix-crystalline urethral plugs o Matrix-crystalline plugs have been found only in male cats o Approximately 84% of matrix-crystalline plugs contain a mineral component o Struvite is present in 80% of these o Urethral plugs have not been observed to occur in dogs o Uroliths occur in both dogs and cats (we will discuss in future lectures) Consequences of urethral obstruction  Consequences of urethral obstruction o Early in course of urethral obstruction . May not be clinically evident . Stranguria, pollakiuria, and inability to urinate may be present . Patient may appear uncomfortable and/or have behavior changes o As obstruction progresses, clinical signs increase in severity . Cat may sit in liter box attempting to urinate or dog may attempt urination and pass only few drops; owners often mistake this sign as constipation . As urine retention continues, post-renal azotemia and eventually uremia develops  Depression, lethargy, moribund state  Vomiting due to uremia  Bradycardia and collapse due to hyperkalemia  Halitosis due to uremia  Death will occur in 72-96 hours after complete obstruction o If urethral obstruction is relieved, cat is likely to recover  The most common abnormalities associated with obstructive uropathy include: dehydration, hyperkalemia, metabolic acidosis, and post-renal azotemia 701

o Dehydration . Fluid therapy is very important in obstructive uropathy because of dehydration and for circulatory support . Remember the 3 components of fluid therapy  Amount for rehydration o % dehydrated x BWkg = L for rehydration  Maintenance o Typically 1 ml/lb/hour (2.2 ml/kg/hour)  On-going losses o Measure or estimate o Some recommend ½ maintenance fluid requirements . You should review types of fluid and routes of administration that are acceptable for managing patients with obstructive uropathy o Hyperkalemia . Management of hyperkalemia with obstructive uropathy is similar to management of hyperkalemia occurring with acute renal failure . Re-establishing urethral patency and fluid therapy is often all that is required as long as arrhythmias are not present  Arrhythmias (bradycardia -> sinoatrial arrest -> ventricular escape beats) typically do not occur until the serum potassium is > 8 mEq/L  Death occurs with potassium concentration exceeds 12-13 mEq/L  3 ways to decrease plasma/blood potassium concentration o Dilute and excrete – fluid therapy or dialysis o Transcellular shift . Glucose . Insulin . Insulin and glucose . Bicarbonate o Counteract effect of hyperkalemia at sino-atrial node . Calcium gluconate Re-establishing urethral patency  Male cats o Male cats may be obstructed with uroliths or matrix-crystalline urethral plugs o In male cats, heavy sedation or anesthesia is required o Position male cats in lateral or dorsal recumbency – dorsal is best o Massage distal urethra while compressing the urinary bladder may dislodge the plug o Perform cystocentesis in order to obtain a diagnostic sample and to decompress the bladder. Do not remove all of the urine so that the bladder can be palpated. A potential complication is urine extravasation, which is uncommon if the procedure is performed correctly. o Urethral patency can be re-established by retrograde flushing the urethra Aftercare once urethral patency is re-established  Re-establishing urethral patency is not the end point o Remove as much of the urine as possible once the cat is un-blocked o The bladder may need to be “rinsed” if there is a lot of particulate matter and/or mucous present in the urine . Use sterile crystalloids or water; do not use glucose containing solutions . Do not infuse antibiotics, anti-spasmodics, anesthetics, or acidifiers into the bladder o Glucocorticoids are not indicated as they increase risk of infection o Systemic antibiotics may be administered if an indwelling urinary catheter is not inserted o Anti-spasmodics (urethral relaxants) may help, but there is little data that they in fact do help . In order to relax the urethra, an alpha-antagonist is administered . Phenoxybenzamine or prazosin can be used . Some people administered a skeletal muscle relaxant; however, diazepam has minimal effect on the urinary tract o An indwelling urethral catheter may be required

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. Indications for an indwelling urethral catheter include  Difficulty in un-obstructing the patient  A large amount of particulate matter and/or mucous despite flushing of the urinary bladder  When there is a high likelihood of re-obstruction  If detrusor atony is present Management of an indwelling urethral catheter  An indwelling urethral catheter should be considered on an individual case basis o Severely ill patients o If difficult to catheterize o Poor urine stream post obstruction o Detrusor atony (atonic bladder)  A urethral catheter should be connected to a closed collection system  Management o Systemic antibiotics should not be administered unless given for some other reason . The risk of bacterial urinary tract infection decreases with antibiotic administration . However, when an infection occurs, the organism has a high degree of resistance . Furthermore, the bacterial organism may invade the upper urinary tract resulting in chronic pyelonephritis o Anti-inflammatory agents – such as an NSAID – may be beneficial as long as renal function is good o With an indwelling catheter, a urethral relaxing agent (alpha blocker: prazosin: 0.25-0.5 mg PO q12-24h; phenoxybenzamine: 1.25-5 mg PO q12-24h) is administered to minimize catheter-induced urethral trauma and irritation o With bladder atony, a drug to stimulate bladder contraction, a parasympathomimetic (bethanechol: 1.25-5 mg PO q8h; metoclopramide: 0.1-0.2 mg/kg PO q8h), is administered  Catheter-associated UTI o Occurs in 50-80% of catheterized patients o Prophylactic antibiotics decrease incidence, but increase likelihood of resistance or of an unusual organism o Prevention: . Use as clean to aseptic technique as possible . Physically separate patients with indwelling catheters from others . Wear gloves and wash hands between patients . Replace catheters when damaged or dirty  Typically, an indwelling urinary catheter is maintained for 2 to 3 days o This is not a hard and fast rule, however o Decision to remove the catheter should be based on the progress of the patient, appearance of the urine, and likelihood that the tight junctions of the detrusor muscle have re-established o Remove if catheter is non-patent, damaged, or contaminated  Post-obstructive diuresis must be addressed o Due to back pressure from the obstructive uropathy being transmitted to the upper urinary tract, a heavy diuresis may develop when the obstruction is relieved o This may be as much 2.4 L per day (most cats urinate 30-40 ml per day) o It is important to adjust fluid intake to match urine output so that dehydration does not occur  Cystostomy catheters may be inserted and used long term o These may be mushroom-tipped catheters or low-profile catheters o Allows for long term, indefinite use Non-obstructive idiopathic feline lower urinary tract disease  There have been dozens of proposed treatments for cats with lower urinary tract disease; very few have undergone evaluation in a randomized controlled clinical trial  Antimicrobial agents o Often administered o Bacterial urinary tract infection is an uncommon cause of lower urinary tract disease in cats <10 years of age occurring in <1% of such cats o If a bacterial infection was present, then the cat would have a diagnosis of bacterial cystitis and not idiopathic lower urinary tract disease

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o Their use is not indicated in cats without a proven bacterial urinary tract infection  Urinary tract antiseptics o Methenamine and methylene blue are not indicated in cats with idiopathic lower urinary tract disease o They may cause side effects such as metabolic acidosis (methenamine) or Heinz body anemia (methylene blue) o Since bacterial urinary tract infections are uncommon in young cats, they are not recommended  Urinary tract analgesics o Phenazopyridine is an over the counter preparation available for use by women with recurrent vaginitis/cystitis o In cats, phenazopyridine causes Heinz body anemia and should not be used  Smooth muscle and skeletal muscle relaxants o Many cats with idiopathic lower urinary tract disease have urge incontinence and inappropriate urination o Propantheline, an anticholinergic agent, minimizes force and frequency of uncontrolled detrusor contractions, but has negligible effect on urethral tone (0.25-0.5 mg/kg PO q12h) . It may be beneficial in some cats . However, one study could not document a benefit o Phenoxybenzamine and prazosin are sympatholytic agents that decrease urethral tone and spasm . Clinical data is lacking as to their efficacy with idiopathic feline lower urinary tract disease . I use for a short time in some cats that strain frequently or that had a urethral obstruction especially if an indwelling urinary catheter was inserted prazosin: 0.25-0.5 mg PO q12-24h; phenoxybenzamine: 1.25-5 mg PO q12-24h o Diazepam and dantrolene are skeletal muscle relaxants that may decrease tone and spasm of the distal urethra . Diazepam has minimal effect on urethral tone (2-5 mg PO q8h) . Dantrolene is more effective (0.15-0.6 mg/kg PO q8h) . Clinical studies are lacking as to efficacy of these drugs in cats with idiopathic lower urinary tract disease . I do not usually use  Anti-inflammatory agents o Glucocorticoids . Have been used historically to decrease inflammation . Several studies have shown no benefit . They are contraindicated in cats with urethral obstruction or those that have indwelling urinary catheters  Risk of urinary tract infection increases in cats with indwelling urethral catheters that receive glucocorticoids  Some cats develop pyelonephritis o Non-steroidal anti-inflammatory agents . There are no clinical studies demonstrating safety or efficacy of use of these drugs in cats with idiopathic lower urinary tract disease o Amitriptyline . A tricyclic antidepressant . May have analgesic properties, stabilize mast cells, and decrease inflammation . In one uncontrolled study, 9 of 15 cats with idiopathic lower urinary tract disease improved with amitriptyline . One controlled study of cats with active lower urinary tract disease showed no benefit and cats receiving amitriptyline had a higher incidence of recurrence of lower urinary tract signs . Goal is to find a dose that will have a calming effect on the cat (begin at 5 mg than increase slowly; most cats require 10-12.5 mg)  Glycosaminoglycans o Cats with idiopathic lower urinary tract disease have decreased concentrations of glycosaminoglycans in their urine o Glycosaminoglycans may have a protectant role at the mucosal-urine interface o Two controlled study\ies, failed to show a difference in clinical signs between a glycosaminoglycan and placebo in cats with idiopathic lower urinary tract disease o Pentosan polysulfate sodium, however, may still have effect (50 mg PO q12h)

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 Dietary modification o In cats with matrix-crystalline plugs or with struvite crystalluria, feeding a “struvite preventative” diet may have some benefit o In one study of cats with idiopathic lower urinary tract disease, cats fed a canned diet had fewer recurrences than those fed a dry diet . However, there were more drop-outs in the canned group for unexplained reasons and if added back in – no difference between diet groups o In another study, there was a dramatic decrease in recurrence of clinical signs when cats with idiopathic cystitis were fed a diet that contained higher levels of omega 3 fatty acids and anti-oxidants  Clomipramine and Fluoxetine o Used for urine spraying / marking behavior o Modifies behavior may have some analgesic effects o Not studied for FIC  Pheromones o Sprays and diffusers o May calm a cat down o 1 study of cats with FIC – no benefit  Multi-modal environmental modification (MEMO) o Cats do not respond to force o Cats are territorial and ‘in control’ o Litter boxes and food should be away from noise and distractions o Cats like to climb, hide, scratch, and hunt – vertical and horizontal space o Cats are clean and self-grooming o Cats are active at night o 1+1 rule – 1 food dish, 1 water bowl, and 1 litter box per cat plus 1 extra o Indoor Cat Initiative: http://www.vet.ohio-state.edu/indoorcat.htm

How do I treat cats with lower urinary tract disease? First episode, urethral obstruction, young cat  Unobstruct  Radiographs, UA (other lab work?)  Indwelling catheter?  Torbugesic?  Diet change (likely)?  Antibiotics (peri-catheterizationEnvironmental and behavioral modification? o If persists or recurs, do additional diagnosticsFirst episode, no urethral obstruction, young cat  Urinalysis (minimum)  Torbugesic?  Diet change (likely)? – usually crystal-related disease (either stones or plugs)  If persists or recurs o Do additional diagnostics o Consider . Diet? . Amitriptyline? . Pentosan polysulfate? . Environmental and behavior treatment First episode, urethral obstruction, older cat  Unobstruct  Radiographs, UA (other lab work?)  Indwelling catheter?  Torbugesic?  Diet change (likely)  Stones? o Struvite: infection vs. non-infection o Calcium oxalate 705

 Matrix-crystalline plug?  Others?  Antibiotics (peri-catheterization)First episode, no urethral obstruction, older cat  Diagnostics  Torbugesic?  Diet change? Most likely – urolithiasis most likely cause (especially calcium oxalate)  If persists or recurs o Torbugesic as needed o Diet? o Amitriptyline? o Pentosan polysulfate? o Environmental and behavior treatment

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