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Seattle Veterinary Specialists Continuing Education Symposium DVM Program April 30, 2017 8am-2:30pm McCaw Hall DVM Program 1 Allen Foundation for the Arts Room DVM Program 2 The Norcliffe Room Time Registration | Continental Breakfast 8am-8:40am 8:40 am Introduction with Dr. Kent Vince Introduction with Dr. Jim Perry 8:50am-9:30am Urinary Laser Applications: Lithotripsy and Ectopic Ureter Ablation Matt Vaughan, DVM, Diplomate ACVIM Topsy, Turvy, Twisty, Turny: Untangling Imaging of Torsions and Volvuluses Alaina Carr, DVM, Diplomate ACVR Head Trauma Management in Veterinary Patients Dani Powers, DVM, Diplomate ACVIM (Neurology) Feline Lymphoma: Review and Update on Treatment Kevin Choy BVSc(Hons) MS DACVIM (Oncology) Minimally Invasive Abdominal Surgery Options Stephen Stockdale, DVM, Surgery Resident Indolent and Less Common Canine Lymphomas Nicolas Szigetvari, DVM 9:40am-10:20am 10:30am11:10am 11:10am12:10pm 12:10pm12:50pm Lunch | Grand Lobby Cell-based Model of Coagulation: A Thromboelastographic Analysis Seung Yoo, MS, MBA, DVM, Diplomate ACVP (Clinical) Canine Intrahepatic Shunts Jim Perry, DVM, PhD, Diplomate ACVIM (Oncology), Diplomate ACVS Antifibrinolytics: A new therapy for bleeding Kelly Blackstock, MS, DVM, Diplomate ACVECC Keeping Up With The Flow of Surgical Extrahepatic Biliary Diseases Jessica J. Leeman, DVM Diagnosis and Treatment of Ureteral Obstruction: A Case Series Danielle Pollio, DVM Updates for Mitral Valve Disease Mikaela Mueller, DVM, DACVIM (Cardiology) 1pm-1:40pm 1:50pm-2:30pm www.svsvet.com 1 Thank you to our Sponsors for 2017! Seahawks Level: Space Needle Level: 2 DVM Speakers 2017: Kelly Blackstock, DVM, MS, Diplomate ACVECC DVM- Colorado State University Internship- Fifth Avenue Veterinary Specialists, NY Residency- Cornell University Diplomate- ACVECC Dr. Blackstock graduated with her DVM in 2006 from Colorado State University, College of Veterinary Medicine. She moved to New York, New York where she completed her small animal rotating internship at Fifth Avenue Veterinary Specialists. Following this, she remained at Fifth Avenue as an emergency doctor. After this, she completed a small animal Emergency and Critical Care residency at Cornell University. She obtained her board-certification in Emergency and Critical Care and returned to Fifth Avenue Veterinary Specialists as a criticalist. During her time there, Dr. Blackstock managed critically ill patients, emergency patients and supervised the emergency service as well as the internship program. Dr. Blackstock has a specialist interests in coagulation and respiratory physiology. In her free time, she enjoys triatholons, cooking, scuba diving and traveling. Alaina Carr DVM, Diplomate ACVR DVM – Washington State University Internship – VCA Animal Referral and Emergency Center of Arizona Residency – University of California, Davis Diplomate- ACVR Dr. Alaina Carr received her veterinary medical degree from Washington State University in 2008. After graduation, she joined a small animal referral and emergency hospital for a year-long internship and then went on to complete a residency in Diagnostic Imaging at the University of California-Davis Veterinary Medical Teaching Hospital. In addition to her clinical duties as a resident, which included clinical and didactic teaching of veterinary students, Alaina taught basic and advanced abdominal ultrasound to veterinarians through continuing education courses. She became board certified by the American College of Veterinary Radiology in 2012 and served as an acting faculty member at the University of California, Davis for 1 year. Throughout her post-graduate training, she has maintained active research projects that have culminated in published peer-reviewed manuscripts. Her particular research interests involve imaging of the feline urinary tract with ultrasound and computed tomography (CT). Dr. Carr is originally from Washington State and is very excited to be back in the Pacific Northwest. She lives with her husband and dog (a Pit Bull mix, Adelaide). In her spare time she can usually be found at the barn with her Thoroughbred, named Eagle. 3 Kevin Choy BVSc (Hons), MS, Diplomate ACVIM BVSc(Hons) – University of Melbourne MS - Washington State Univesrity Internship – Oregon State University Residency – Washington State University Diplomate ACVIM (Medical Oncology) Dr. Kevin Choy received a Bachelor of Veterinary Science from the University of Melbourne, Australia in 2006 with first class honors, after earning a Bachelor of Science degree in Animal Science from the University of British Columbia, Canada in 2003 with honors. He worked in small animal private practice in the heart of Melbourne, Australia before pursuing specialist training back in the United States. He completed an internship in small animal medicine and surgery at Oregon State University in 2009 and a Masters degree and residency in small animal medical oncology at Washington State University in 2013. As a resident at Washington State University, Dr. Choy received multiple honors including the Thibodaux Oncology Award, Strickler Award in Oncology, and Pera Scholarship in Oncology in addition to resident of the year distinction. He is a board certified specialist in medical oncology as a diplomate of the American College of Veterinary Internal Medicine (ACVIM). While in Melbourne, Dr. Choy has also served as an emergency relief veterinarian on behalf of Wildlife Victoria to assess and treat injured Australian fauna including Koalas, Wombats and Kangaroos as well as provide veterinary access to aboriginal communities in Australia. Dr. Choy's professional interests include lymphoma, transitional cell carcinoma, localized tumor treatment with electrochemotherapy and translational cancer research through cooperative clinical trials and research projects with both local and national institutions including the Fred Hutchinson Cancer Research Center to improve patient care in both animals and their owners. He has presented both at national cancer conferences and continuing education seminars with research at Washington State University investigating transitional cell carcinoma therapy in dogs and has co-authored studies and book chapters in feline lymphoma and mammary tumors. In his spare time, he enjoys spending time with his wife, two children and two cats. Personal interests include wildlife photography, Kendo, following his hometown hockey team (Vancouver Canucks) and traveling the Pacific Northwest. Jessica Leeman, DVM, Diplomate ACVS-SA DVM - University of Florida Internship - Louisiana State University Surgery Internship - Seattle Veterinary Specialists Residency - Seattle Veterinary Specialists Dr. Jessica Leeman received her bachelors degree from Florida Atlantic University followed by veterinary school at the University of Florida and a rotating internship at Louisiana State University. She completed her surgery residency at Seattle Veterinary Specialists and is now a Diplomate of the American College of Veterinary Surgeons. Her affinity for small animal surgery began in freshman anatomy and has since developed into a passion for correcting, and sometimes curing surgical diseases. Her current interests include surgical oncology and reconstructive procedures. Jessica enjoys yoga, weightlifting, and camping during her spare time. She resides in Kirkland with her fiancé, son, and Yorkie, Scoop of Ice Cream. 4 Mikaela Mueller, DVM, Diplomate ACVIM DVM - Tufts University, North Grafton MA Bachelor of Science, Zoology - Miami University, Oxford OH Internship - Small Animal Medicine & Surgery, Advanced Veterinary Care Center, Lawndale CA Residency - University of California, Davis Dr. Mikaela Mueller has always related well to animals. Her interest in biological sciences and medicine grew throughout her schooling. She also likes the idea that she can apply those interests to helping animals and the people who love them. Her interest in cardiology stems from the fact that she likes the mechanics of the heart and she is fascinated by the many imaging modalities available for diagnostics. Dr. Mueller’s clinical interests include complex heart disease and the management of acquired cardiac disease and congestive heart failure. She enjoys being active and outdoors, including hiking and athletic pursuits such as riding her horse, Ollivander. She also enjoys quiet time at home and spending time with her family, her husband, three dogs and a cat. Jim Perry, DVM, PhD, Diplomate ACVIM, Diplomate ACVS-SA DVM - Colorado State University PhD - Colorado State University Oncology Residency - Colorado State Univeristy Diplomate ACVIM (Oncology) Surgery Residency - Aspen Meadow Veterinary Specialists Diplomate ACVS-SA Dr. Perry, originally from Portland, Oregon, received his Bachelor's degree in biochemistry and cellular biology at the University of Washington in Seattle. He then went on to complete his veterinary medical degree and PhD in cellular immunology at Colorado State University. After working in private practice for a year, he returned to the clinics at CSU for his residency in medical oncology followed by a surgical residency at Aspen Meadow Veterinary Specialists. Dr. Perry's clinical and research interests include comparative cancer biology, immunology, targeted chemotherapeutics, and surgical oncology. Dr. Perry is a diplomate of the American College of Internal Medicine (ACVIM) and the American college of Veterinary Surgeons (ACVS). He is a member of the American Veterinary Medical Association, Veterinary Orthopedic Society, Veterinary Cancer Society, Veterinary Society of Surgical Oncology and the American Association of Immunologists. In his free time, Dr. Perry enjoys biking, kayaking, and back country skiing with his Tolling Retriever and Border Collie. 5 Danielle Pollio, DVM DVM- University of Georgia Small Animal Rotating Internship- Red Bank Veterinary Hospital Residency- BluePearl Veterinary Partners, Tampa, Florida Dr. Danielle Pollio grew up in a suburb near Atlanta, Georgia. She attended the University of Georgia College of Veterinary Medicine, from which she graduated magna cum laude and was awarded the Dean Emeritus Thomas J. Jones Cup for outstanding professional proficiency and scholastic achievement. During her time at UGA, Dr. Pollio gained strong experience caring for animals in the intensive care unit and volunteered with the HSVMA to provide veterinary services to underserved rural communities. After veterinary school, Dr. Pollio completed a small animal rotating internship at Red Bank Veterinary Hospital and went on to pursue a three-year residency in emergency and critical care medicine at BluePearl Veterinary Partners in Tampa, Florida. Dr. Pollio enjoys all aspects of emergency and critical care and is particularly interested the treatment of polytrauma and sepsis. In her free time, you may find Dr. Pollio biking along the Burke-Gilman trail with her family, dining at one of Seattle’s great restaurants, or simply relaxing at home with a good book. Dani Powers, DVM, Diplomate ACVIM (Neurology) DVM - Washington State University Internship - Seattle Veterinary Specialists Residency- Seattle Veterinary Specialists Dr. Powers received her bachelor's degree at Washington State University and then continued to complete her Doctorate of Veterinary Medicine at Washington State University in 2011. She completed a small animal rotating internship at Seattle Veterinary Specialists in 2012. Dr. Powers completed a Neurology and Neurosurgery Residency at Seattle Veterinary Specialists. Her areas of interest include seizure management, neurosurgery and physical rehabilitation techniques following neurosurgical interventions. Dr. Powers enjoys spending time with her family including her husband Jon and children as well as their two cats Tux and Moto. They like to explore the Pacific Northwest including the great hiking, local sports, food, and wine. Stephen Stockdale, DVM DVM- Washington State University College of Veterinary Medicine Small Animal Rotating Internship- Seattle Veterinary Specialists, Kirkland Residency- Seattle Veterinary Specialists, Kirkland Dr. Stephen Stockdale grew up in the eastside of Seattle. He attended Washington State University from 2005-2008 where he graduated magna cum laude with a Bachelor of Sciences degree in Animal Sciences with a minor in Biology. After graduating, he spent a year working in a general veterinary practice before attending Washington State University College of Veterinary Medicine and obtained his DVM in 2013. His interests are minimally invasive surgery with laparoscopy and thoracoscopy as well as soft tissue surgery. Dr. Stockdale completed his rotating internship at SVS and stayed with SVS for a surgical residency beginning in July, 2014. In his free time, Dr. Stockdale enjoys traveling, road cycling, bike touring, mountain biking, rock climbing, fly fishing, and running with his dogs. 6 Nicolas 'Nick' Szigetvari, DVM, Practice-Limited to Oncology DVM - University of Illinois Internship - University of Wisconsin Residency - Purdue University Dr. Szigetvari received his DVM from the University of Illinois. Following his DVM, Dr. Szigetvari was in general practice for several years then decided to continue his training and specialize. He completed a small animal rotating internship at the University of Wisconsin. Following his internship, Dr. Szigetvari went on to complete an oncology residency at Purdue University. Matt Vaughan, DVM, Diplomate ACVIM (SAIM) DVM - University of California Davis Internship - Texas A&M University Residency - University of California Davis Diplomate ACVIM (SA Internal Medicine) Dr. Matt Vaughan is originally from Philadelphia, Pennsylvania. He attended the University of California, Santa Cruz for his undergraduate schooling where he graduated with highest honors in 1997. After some well spent time traveling and exploring the world, he attended veterinary school at the University of California, Davis (UCD) and graduated in 2004. He then completed a one year small animal internship at Texas A&M University before returning to UCD for a small animal internal medicine residency between 2005 and 2008. At UCD, Dr. Vaughan served as chief resident during the third year of his residency. After receiving his board certification in Internal Medicine, Dr. Vaughan joined Seattle Veterinary Specialists in 2008. Dr. Vaughan holds a special interest in endocrinology and spent much of his residency involved in research projects focused on canine Cushing's disease and diabetes mellitus. He also has an interest in interventional radiology and performs procedures such as tracheal, urethral and ureteral stents. Seung Yoo, MS, MBA, DVM, Diplomate ACVP (Clinical) Bachelor of Science, Master of Science - University of California at Davis DVM- Colorado State University MBA- Colorado State University Small Animal Rotating Internship- Michigan State University Residency- Colorado State University Dr. Seung Yoo grew up in South Pasadena, a quiet suburb in balmy Southern California. He received both a Bachelor of Science and a Master of Science at the University of California at Davis. After graduating from Colorado State University in 2010 with a combined MBA/DVM degree, he arrived at Michigan State University for a one year small animal rotating internship. He then completed a Clinical Pathology residency at Colorado State University in 2014 with additional training in Anatomic Pathology and accepted a position as a Clinical Pathologist at Seattle Veterinary Specialists. His professional interests include hemostasis, mineral metabolism, and autoimmune diseases. When not at work, he enjoys spending time with his wife, dog, and two cats. His hobbies include wood working, skiing, snowboarding, rock climbing, hiking, bread baking,brewing beer, fishing, and ice hockey. 7 Urinary Laser Applications: Lithotripsy and Ectopic Ureter Ablation Matt Vaughan, DVM, Dip ACVIM Internal Medicine Seattle Veterinary Specialists Seattle, WA LASER LITHOTRIPSY Uroliths are a common cause of urinary tract obstruction, irritation and a complicating factor of urinary tract infections in cats and dogs. Although some types of calculi can be dissolved, many need to be physically removed. Traditionally, cystotomy has been the treatment of choice for urocystoliths and if urethral calculi are present they are retropulsed into the bladder to allow removal via cystotomy. For cases where calculi cannot be retropulsed to the bladder, urethrostomy is an option to relieve obstruction. Lithotripsy is a procedure where calculi are broken into small fragments and literally means “breaking of the stone”. Lithotripsy can be performed by applying external shock waves (extracorporeal shock wave lithotripsy) or can be performed by using a laser directly on the calculi via endoscopic guidance. Shock wave lithotripsy is utilized in some facilities for fragmentation of small nephroliths (NOT available at SVS). Laser lithotripsy utilizes a Holmium:YAG laser. The laser energy is transmitted using flexible quartz fibers passed through the working channel of a cystoscope or nephroscope. The laser energy is absorbed in <0.5mm of fluid, which allows for stone fragmentation with minimal risk of damage to surrounding tissue. The Ho;YAG laser can fragment all types of uroliths. This laser can also be used if desired to cut tissue that it is directly in contact with. Stone fragmentation is via a photothermal effect (thermal drilling) as opposed to shock waves. This photothermal effect may change stone composition of small fragments however stone analysis is typically reliable on retrieved fragments. Lithotripsy is used to fragment the uroliths to a size that can be removed through the urethra. These fragments are then removed via a combination of basket retrieval and urohydropropulsion with the goal being removal of all fragments. Fragments are then submitted for stone analysis. Benefits of laser lithotripsy include a success rate equaling cystotomy as well as a reduced recovery time and no incision care. Complication rates are low with lithotripsy and are comparable to or lower than with cystotomy. Possible complications include anesthetic complications, urethral swelling, hematuria, inability to remove all fragments, urethral tear or bladder rupture. Lithotripsy does require general anesthesia and depending on the size and amount of stones present may take as long as or longer than surgery. For this reason, the best candidates for lithotripsy are those with smaller or fewer stones. Lithotripsy can be performed on an outpatient basis however it is typically recommended that they spend the night after the procedure to monitor for any difficulty urinating as well as treat any pain or irritation. 8 Laser lithotripsy can be performed in male and female dogs as well as female cats. It is not possible in male cats due to the small urethral size. Small male dogs (<5kg) may not be possible due to small urethral size (the urethroscope is 7.5fr). Prior to attempting the procedure in small male dogs, an 8fr red rubber catheter is placed to ensure adequate urethral diameter to accommodate the scope. Given the small urethral size and cystoscope limitations, male dogs are more difficult and male candidates are best limited to those with a very small stone burden. Stones that are within the male urethra are good candidates and can be treated easily with lithotripsy (as long as there are not a large amount of urocystoliths present as well). Laser lithotripsy cannot be performed on stones in the ureter or kidney using a cystocopic approach (see below). The Holmium:YAG laser can also be utilized for other non-invasive urologic procedures including polyp removal, debulking of urethral tumors and ectopic ureter ablation. Indications Candidates Complications Urocystoliths Female dogs Inability to remove all fragments Urethroliths Male dogs (8fr red rubber catheter able to pass) Urethral/bladder tear Female cats Transient stranguria/hematuria Low stone burden Incontinence Nephroliths can be removed via surgery, extracorporeal shock wave lithotripsy (if small) or percutaneous nephrolithotomy (PCNL). PCNL involves placement of a wire into the renal pelvis via ether a percutaneous or surgically assisted approach. A tract is dilated over the wire with a balloon and a sheath is then put in place through which a nephroscope is advanced. Lithrotripsy is then performed using a laser or ultrasonic lithotripter and fragments are extracted through the sheath. This procedure results in less nephron damage than traditional surgical approaches. This procedure is not currently being offered at SVS however may be in the future. Nephroliths are typically only removed if causing obstruction or causing recurring urinary tract infections and attempts at dietary dissolution is recommended prior to consideration of removal. ECTOPIC URETERAL LASER ABLATION Ectopic ureteral ablation is a non-invasive procedure performed through the cystoscope to correct ectopic ureters with a success rate equals traditional surgery but has the benefit of being performed as an outpatient procedure with faster recovery. This procedure can be performed to correct intramural ectopic ureters however cannot be performed if the ectopic ureters are extramural. Cystoscopy is typically utilized to confirm and identify types of ectopic ureters prior to surgery. Laser ablation can be performed at the same time the diagnosis is made. A retrograde ureterogram is performed during cystoscopy using fluoroscopic guidance to confirm that the ureter is intramural and identify location where the ureter leaves the bladder wall. The laser fiber is then advanced through the 9 working channel of the cystoscope and the luminal wall of the ectopic ureter is ablated under direct visualization to move the ureterovesicular junction to within the bladder. Success rate has been reported at 53% with ablation alone, which is similar to surgical success rates. Failure of this procedure, as with surgical procedures, is due to concurrent causes of incontinence (urethral sphincter mechanism incontinence, urethral hypoplasia, etc). For dogs that are not successfully treated with ablation alone, the addition of medical therapy (phenylpropanolamine, estrogen) and /or urethral occluding device improves success rate to 77%. Indications Candidates Complications Ectopic ureters Female dogs Continued incontinence Can be performed at time of initial diagnosis Male dogs >10kg Urethral/bladder perforation REFERENCES Bevan JM, Lulich JP, Albasan H, Osborne CA. Comparison of laser lithotripsy and cystotomy for the management of dogs with urolithiasis. J Am Vet Med Assoc. 2009 May 15;234(10):1286-94. Lulich JP, Osborne CA, Albasan H, Monga M, Bevan JM. Efficacy and safety of laser lithotripsy in fragmentation of urocystoliths and urethroliths for removal in dogs. J Am Vet Med Assoc. 2009 May 15;234(10):1279-85. Grant DC, Werre SR, Gevedon ML. Holmium: YAG laser lithotripsy for urolithiasis in dogs. J Vet Intern Med. 2008 MayJun;22(3):534-9. Berent AC, Weisse C, Mayhew PD, Todd K, Wright M, Bagley D. Evaluation of cystoscopic-guided laser ablation of intramural ectopic ureters in female dogs. J Am Vet Med Assoc. 2012 Mar 15;240(6):716-25. Berent AC, Mayhew PD, Porat-Mosenco Y. Use of cystoscopic-guided laser ablation for treatment of intramural ureteral ectopia in male dogs: four cases (2006-2007). J Am Vet Med Assoc. 2008 Apr 1;232(7):1026-34. Reichler IM, Eckrich Specker C, Hubler M, Boos A, Haessig M, Arnold S. Ectopic ureters in dogs: clinical features, surgical techniques and outcome. Vet Surg. 2012 May;41(4):515-22. 10 Head Trauma Management in Veterinary Patients Dani Powers DVM, DACVIM Neurology Seattle Veterinary Specialists Kirkland, WA Clinical Presentation: The veterinary patient that presents with head trauma most commonly is secondary to an incident with a car, however there are several causes that can lead to head trauma. o o o o o Animal bite wound Impact Falling Gunshot wound Unknown Trauma If head trauma is suspected then patients should be handled very carefully. A thorough triage history and basic database can be used to help evaluate these patients. Triage: A good history includes questions about consciousness after the incident (or at the present time), mentation status (see below), presence of seizures, when the incident occurred, any other illness or comorbidities (fractures, abdominal or thoracic wounds, etc.). Diagnostics: The following diagnostics should be performed on patients with suspected head trauma. During handling, it is important to minimize stress and avoid causing a patient to struggle. Sedation and general anesthesia are generally contraindicated unless absolutely necessary. Managing pain (if needed) with opioid drugs may be helpful in handling these patients, and not cause too much sedation or hypotension. - CBC and Serum Biochemical Profile; avoid jugular venipuncture as compression of the jugular vein can increase intracranial pressure. Blood Pressure(s) (preferably with a Doppler Unit) Blood Gases or SpO2 (pulse oximetry) Urinalysis Assess for other wounds and treat as needed (chest radiographs, abdominal ultrasound to look for free fluid) Neurologic evaluation in the triage setting (preferably done prior to any medications); evaluate pupil size, pupil symmetry and responsiveness to light, assess the mentation status (is the patient alert, quiet, depressed, obtunded, stuporous, or comatose), assess the ambulatory status of the patient. o Alert: The patient is mentally appropriate. They are responsive to external stimuli. o Quiet: The patient is mentally appropriate. They are responsive to external stimuli, although not as robustly in the alert patient. 11 - o Depressed: The patient is not mentally appropriate for the situation. They are still responsive to stimuli, but more likely require direct stimulation. o Obtunded: The patient is not mentally appropriate. They require more vigorous stimulation to have a response. They may seem disoriented or confused. o Stuporous: The patient is not mentally appropriate and appears unconscious. They are minimally responsive to external stimuli. With aggressive noxious stimuli, they should respond. o Comatose: The patient is non-responsive to any stimuli. They are unconscious. Advanced imaging of the brain. o Usually an MR brain scan is the imaging modality of choice; however, CT scans may also be utilized to view the boney structures for fractures. This should be performed only if needed and after cardiovascular stabilization. Both require general anesthesia and should be avoided in the immediate period unless the patient is declining. o Radiographs can sometimes be useful to identify a skull fractures, but are often hard to interpret and may require sedation to achieve diagnostic films, and as previously mentioned sedation should be avoided unless absolutely necessary. Treatment: Treatment for the acute head trauma patient will depend on the patients’ status and comorbidities. Many patients are in cardiovascular shock and with general treatment for this they can improve dramatically. Remember that severe shock and hypotension can lead to a patient that is mentally dull and weak. Simple treatments with IV fluids and oxygen support can go far to ameliorate the abnormal mentation changes. - IV Catheter(s). Place a large gauge catheter to facilitate quick and effective fluid delivery. o Cats: 22-20 gauge o Dogs Less than 10kg: 22-20 gauge o Dogs 10-20kg: 20-18 gauge o Dogs greater than 20kg: 18 gauge or larger. - IV Fluids; dose and rate will be determined by patient status, blood pressure and exam findings. o Typically, a ¼ shock dose is utilized initially and then the patient is reassessed for the above-mentioned parameters. o Additional boluses are utilized as deemed necessary. o Normal shock dose is 90ml/kg for dogs and 60ml/kg for cats of isotonic fluids (plasmalyte, LRS, Normosol R) - Oxygen; supplemental flow-by, nasal cannulas and endotracheal intubation are the best at providing oxygen as opposed to closed cage oxygen chambers. o Patients with head injury are more likely to require constant monitoring and oxygen chambers would not be ideal in these situations. o A pulse oximeter reading of greater than 90, and even more so greater than 95 should be the goal in these patients. 12 o If flow-by is not adequate in maintaining pulse oximetry reading at the above values then sedation and endotracheal intubation should be considered. - Controlling Increased Intracranial Pressure o Hypertonic saline 5ml/kg IV over 5-20 minutes depending on mental status o Mannitol 1gram/kg or 5ml/kg of 20% Mannitol over 10-20 minutes +/- furosemide at 1mg/kg 15 minutes later o Raise head to 30 degrees to help decrease intracranial pressure. - Control seizures; valium 0.5mg/kg IV to effect (see below in seizure section). - Maintain carbon dioxide status o If intubated ventilate to keep CO2 between 25-30 mm Hg (PaCO2) or as measured by End Tidal CO2 monitors, which prevents excessive brain vasodilation thereby decreasing ICP. Excessive hyperventilation can cause brain vasoconstriction which can also be deleterious and lead to decreased cerebral perfusion pressure and brain ischemia. o Blood gases if available, can also be utilized to evaluate CO2 status in the patient. - Maintain Cerebral Perfusion Pressure (CPP); which is characterized by CPP=Mean Arterial blood pressure –Intracranial blood pressure. o Maintaining cerebral perfusion pressure will help to maximize cerebral metabolic functions and minimize secondary brain injury. o This is difficult to measure and not often done in veterinary clinical practice. o CPP is best managed between certain systolic blood pressure values, which are easier to monitor. Ideally trying to maintain blood pressure between 80-150mm Hg systolic will aid in normal cerebral perfusion pressure. - Recumbency care. o Recumbency care should be performed every 4 hours. Flipping the hips can be done if the patient is remaining sternal, or a complete flip if they do not stay sternal. o Avoid flipping in the short-term assessment of the patient if there is a suspicion for spinal fracture. - Bladder care o A urinary catheter can be placed easily in male dogs to quantify urine, and with some practice female dogs can also be catheterized. o Use of a Foley catheter connected to a closed system collection bag is the most helpful for maintaining sterility and allowing quantification. o If a urinary catheter is not possible then use gentle bladder expression every 6-8 hours. o Patients that are conscious can probably urinate on their own and may resist bladder expression. o Corn starch can be used safely used to prevent or help treat urine scald. o Placement of absorbent pee pads is important to prevent urine scald. 13 - Controlled Hypothermia o Rectal temperatures between 91-95 degrees Fahrenheit may be beneficial in some cases of head trauma. o Cooling may help to decrease seizures and intracranial pressure, as well as decrease cerebral metabolic rate. o In addition, cooling can help decrease inflammatory cascades that add to secondary bran injury and help to maintain the blood brain barrier. o The literature in animals has utilized controlled hypothermia in the face of intractable seizures that did not respond adequately to pharmacologic intervention. o In human medicine controlled cooling has been utilized in the emergency setting if there is history of head trauma and/or if the intracranial pressure is elevated. o The most recent information in humans (brain trauma foundation) does not suggest cooling of patients with head trauma as there are studies supporting and refuting this medical procedure without a clear consensus. o Controlled cooling should only be performed under direct supervision of a veterinarian and is not substantiated at this time as a first line of defense in acute head trauma patients. o Ideally cooling is done to normal temperatures and not below. Patients that are normothermic should avoid being overheated. - Anti-inflammatories (Steroids) o Multiple different steroids have been utilized to help decrease intracranial pressure in patients with head trauma. o This is not a first line defense for treating head trauma patients in human medicine as studies have not shown significantly different outcomes with patients receiving and not receiving steroids. o Some studies have shown increased mortality rates in patients receiving steroids in human literature. o Most human studies have focused on high dose therapy as opposed to low dose therapy. There may be some desirable effect at lower dosages. o Simultaneous use of gastroprotectants such as famotidine or pantoprazole should be considered. (Later oral formulations such as omeprazole, sucralfate, and misoprostol may be used if GI side effects are recognized). - Pain management o Most opioids are adequate, with the exception of buprenorphine, which is not easily reversed in cases of declining cardiovascular or mental status. - Preventing Pressure Sores o Avoid shaving over boney prominences o Fur provides protection to these areas and helps to avoid pressure sores from developing. o Recumbency care becomes very important to help prevent pressure sores. 14 - Nutrition o Oral feeding, including water, is often postponed until the patient can adequately prehend food and swallow effectively. o Check a gag reflex or monitor for normal tongue movement if not allowing gag reflex prior to oral medications, food or water. o Feeding by the 7th day following brain injury in people has been associated with lower mortality rates. o Optional feeding routes may include nasogastric tubes or parenteral nutrition. - Preventing Aspiration Pneumonia o Suction mouth as needed for excessive saliva, gastric reflux, blood, etc. o Gentle suctioning and oral care is important to prevent laryngeal/pharyngeal damage. o Avoid oral administration of food, water or PO medications until the patient can swallow on their own. Level of alertness also plays a role in the timing of oral feedings. o Clean and rinse mouth every 2-4 hours, or as needed. o If aspiration is suspected or known to have occurred then consider broad spectrum antibiotics to treat secondary infection. In addition, nebulization may be added, with controlled coupage if the patient is deemed OK to have that procedure performed - Prevent Corneal Ulcers o Lubricate eyes every 2-4 hours or as needed to maintain hydration in patients that are not blinking spontaneously. o Monitor closely for presence or appearance of corneal ulcers; treat accordingly. - Multiple other medications and treatments have been utilized with equivocal success. These may or may not be helpful and are clinician’s preference when using as a treatment for head injury. o Calcium Channel blocking drugs, NMDA antagonists, CSF drainage Types of Injury Occurring in the Brain: - - - Primary brain injury occurs at the time of impact and is due to direct impact to the brain parenchyma including contusions, lacerations, and diffuse axonal injury. Damaged blood vessels can lead to intracranial hemorrhage and vasogenic edema. Secondary brain injury occurs following the impact and is a result of a domino effect of biochemical pathways that lead to depleted energy supply, increase in free radical production and increases in intracranial pressure. Edema o Cytotoxic edema occurs with hypoxia and ischemia and leads to decreased energy supply to the cells (ATP) leading to failure of Na – K pumps and eventually causes fluid to rush into the cell causing swelling, release of excitatory neurotransmitters (glutamate), increase intracellular calcium results leading to initiation of the proinflammatory and oxidative pathways and eventually cell death o Vasogenic edema occurs when there is breakdown of the blood brain barrier leading to extravasation of protein rich fluid 15 - Hemorrhage can cause immediate and delayed effects. Ischemia/hypoxia Secondary infection from penetrating wounds is also possible which can further exacerbate brain damage. Seizures: - - - Seizures following traumatic brain injury are common in people and also in dogs. Immediate post-injury seizures are common as well as in hospital (prior to discharge) seizure activity. Post discharge seizure activity can occur up to 4 years following the brain injury. The longer the patients go without seizures, the less likely they are to develop seizures. Main treatment consists of anti-convulsant medications (valium, lorazepam, phenobarbital, Keppra,) o Valium 0.5mg/kg IV to effect (5mg/ml concentration valium; approximate doses: 1ml small, 2ml medium, 3ml large) +/- Valium CRI Other treatments may include propofol and general anesthesia for intractable seizures. o Propofol has been shown to have neuroprotective effects and so may be useful on many levels for patients with head trauma. o General anesthesia with isoflurane gas can double intracranial pressure and should be avoid unless absolutely necessary for patients with head trauma. Long term seizure management is usually continued in cases of known seizure activity following head trauma. In some cases, this can be tapered if the patient is seizure free for greater than 6-12 months while on medications. Prognosis: - - Modified Glasgow Coma Score o This is an objective measurement of the alertness of the patient and the level of consciousness. o It has been modified from the commonly used human Glasgow Coma Score, which is an algorithm to guide treatment and prognosis in patients with head injury. o Not as commonly used in veterinary patients, but can be used in prospective or retrospective studies as an objective evaluation of patients. The prognosis depends on the injury sustained, how long the injury occurred before medical intervention and the treatment options available to the patient. In people the prognosis is significantly correlated with the level of oxygenation and systolic blood pressure prior to and during medical intervention. Head trauma in veterinary patients carries and excellent to guarded prognosis depending on the degree of injury. 16 Degree of Recovery - - - The degree of recovery in humans is measured by the outcome of the patient functionally. From normal, to mild neurologic deficit, severe neurologic deficit, and death. In veterinary patients, the degree of recovery may be less important if they can perform the tasks required as a companion animal, as opposed to a working animal or person for that matter. Some veterinary patients may have recognizable deficits and some may have subclinical deficits. Our patients do not need to re-learn to speak, balance a checkbook, or drive a car and so the level of functionality tends to be less important. Good quality of life is most commonly based on degree of comfort, willingness to eat and drink, ability to get around (walk), and general behavior and attitude. Furthermore, time is often a very important tool for any patient with neurologic dysfunction and the ability to improve. 17 Modified Glasgow Coma Score: - There are three levels of evaluation for the MGCA including motor function, brainstem reflexes and level of consciousness. A prognosis can be applied to the MGCS. - Platt 2001 - 18 Important Take Home Points: - Immediate action with IV fluid support to maintain normal blood pressure, as well as supplemental oxygenation is critical for patients that have sustained head injury. Prevent hypoxia, hypotension, hypercarbia and hypovolemia. By preventing the hypovolemia and hypoxemia secondary to shock often the brain function will improve without necessarily treating the brain trauma directly. Supportive care and time are of utmost importance in patients with head trauma and brain injury. The post injury supportive care and attention to detail will make the difference between patients that leave the hospital and those that do not. References 1. Badjatia N, Carney N, Crocco TJ, Fallat ME, et al. Prehospital Emergency Care. Official Journal of the National Association of EMS Physicians. January / March 2007. Supplement to Volume 12 / Number 1. 2. Carney N, et. al. Guidelines for the management of severe traumatic brain injury. 4 th Edition. Brain Trauma Foundation September 2016. Braintrauma.org 3. Chen JWY, Ruff RL, Eavey R, Wasterlain CG. Posttraumatic Epilepsy and Treatment. Journal of Rehabilitation Research and Development. Vol. 46 No. 2009, pp 685-696. 4. Freidenberg SG, Butler AL, Wei L, Moore SA, Cooper ES. Seizures following head trauma in dogs: 259 cases (1999-2009). JAVMA, Vol 241, No. 11, December 1, 2012. 5. Hayes GM. Severe seizures associated with traumatic brain injury manages by controlled hypothermia, pharmacologic coma, and mechanical ventilation in a dog. J Vet Emerg and Crit Care. 19(6) 2009, pp 629634. 6. Fox JL, Vu EN, Doyle-Waters M, Brubacher JR, et al. Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review. CJEM 2010; 12(4):355-364. 7. Garosi L, Adamantos S. Head trauma in the cat. Assessment and management of traumatic brain injury. J of Feline Medicine and Surgery. (2011) 13, 815-823. 8. Sande A, West C. Traumatic brain injury: a review of pathophysiology and management. J of Emerg and Crit Care. 20 (2) 2010, pp 177-190. 9. Platt SR, Radaelli ST, McDonnell JJ. The Prognostic Value of the Modified Glasgow Coma Scale in Head Trauma in Dogs. J Vet Intern Med 2001; 15:581-584. 19 Laparoscopic Surgery Stephen Stockdale DVM Seattle Veterinary Specialists Kirkland, WA Introduction While we think of laparoscopy as being high-tech and relatively novel, multiple renditions have been present through multiple era. Hippocrates used a simple speculum for rectal exams in 460-377BC.1 German physician Phillip Bozzini developed the Lichtleiter (light conductor) for inspection of cervix, urethra, rectum, nasal cavity, ears, etc. in the late 1700s.2 This instrument utilized a wax candle as a light source and was an advancement of the simple speculum. In the late 1800s, French urologist Antoine Jean Desormeaux modified Bozzini’s Lichtleiter by adding a mirror to reflect light from a kerosene lamp through a metal channel tube and named it “endoscope.” In the 1930s Janos Varess developed the spring loaded varess needle to create pneumothorax for patients with tuberculosis. Laparoscopists realized the potential of the instrument to create a safe pneumoperitoneum. In the mid 20th century (1940-1960), there was a lag in progression due to controversy associated with complications of insufflation and electrocautery equipment. None the less, progress continued on. Kurt Semm was highly progressive and developed intracorporeal knot tying techniques, loop applicators, as well as a pressure regulated insufflator. He was highly criticized for his first appendectomy; as it was considered unethical. His colleagues questioned if he had truly even performed the procedure or if it were a hoax. His medical license was challenged by his colleagues. The first laparoscopic cholecystectomy was performed by Erich Boblingen in 1985 and ignited the interest in laparoscopy application in humans. It is now the preferred technique in humans. Veterinarians followed soon thereafter. Veterinary endoscopy did not follow such a controversial path. Veterinary laparoscopy really started growing in the 1970’s with purely diagnostic techniques. Dr. Rawlings and Freeman were some of the pioneers to laparoscopic and laparoscopic-assisted techniques in veterinary medicine in the later 90’s and early 2000’s. Dr. Eric Monnet founded the Veterinary Endoscopy Society in 2003 which gathers annually around the world to share experiences and advancements in the field. Annual attendance continues to steadily rise. Laparoscopy is now being taught in multiple academic and private practice residency programs. Benefits There are a multitude of reasons why laparoscopy can be favored over a traditional open approach. The most notable difference is the size of the incisions. With smaller incisions, postoperative incision site dehiscence carries a less severe consequence compared to a traditional open surgical approach. This is especially important for patients with anticipated delayed wound healing (chronic renal failure, hyperadrenocorticism, hypoproteinemia). With smaller incisions, it has been shown time and time again that postoperative pain is decreased.3-5,20 This has been shown in human surgery as well as veterinary surgery based on visual analog scores, serum cortisol levels, blood glucose levels, accelerometers and direct pressure tolerance. Smaller incisions also take a shorter amount of time to close. Laparoscopy offers the advantage of significant magnification to the surgeon. This offers both enhanced detail of the organs being observed but also improved visualization of tissue planes when dissecting between vital structures. Certain dyes (indocyanin green) can be utilized to highlight certain structures introperatively with the appropriate video systems. 20 Laparoscopy can be both diagnostic and therapeutic. True abdominal and thoracic explores are possible with very little patient morbidity compared to open laparotomy/thoracotomy. This can be performed initially to determine if surgery is warranted prior to conversion to a traditional open procedure or performing a laparoscopic/thoracoscopic procedure. Operation times can be shortened for some procedures with laparoscopy compared to open procedures. Once proficient in laparoscopy, surgical times end up being similar. Clients are asking for this modality more and more with the increased use in human medicine. People want the same options for their pets that they are offered. Clients tend to appreciate the smaller scar line. Because of smaller incision sites, there has been shown to be a decreased risk of surgical site infections for clean contaminated minimally invasive surgeries. Because of this, antibiotics are rarely used outside of the perioperative period. Detriments There is a steeper learning curve for laparoscopic surgery due to the use of long instruments through small channels. This causes hand movements to be awkward initially. For single incision laparoscopy (SILS, Covidien Medtronic, MN), instruments are positioned very close and can cross over within the body cavity. This has led to the development of articulating and roticulating instruments which add additional hurdles to overcome. There is a loss of tactile sensation (haptic feedback) with long metallic instruments that you don’t have with open surgery. Typically, an assistant is needed to manipulate the camera which can make laparoscopy application in a general practice more difficult. This leads to no personal bubble by any means. Additional difficulty comes from inherent monocular vision associated with a camera screen (That being said, a threedimensional camera system has recently become available). Remember, laparoscopy strives to transfer discomfort away from the patient and inherently transfers it to the surgeon. Equipment cost can be significant (See below). Unfortunately, this does translate into higher costs for our customers. Interestingly, as our clients become more informed, they are willing to pay the extra cost in most cases for the more rapid recovery. This was documented in one study where 90% of clients polled preferred laparoscopic approaches to surgery if available and 78.3% of clients polled would pay between $800-$2000 more over a traditional surgical approach.21 While operating time can be reduced in many cases, it is typically prolonged initially when first learning. The decreased postoperative morbidity of the patient still outweighs the increased surgery time in my eyes. Surgeon skills The basic skills necessary for any new laparoscopist are ambidexterity, hand-eye coordination, instrument accuracy, and determining a sense of depth.2 This all stems from the fact that you are utilizing monocular vision in a tight space with long instruments working against a fulcrum. It is important to be precise in movement because any small movement out of the body can be translated into a large one within the abdomen. Additionally, any instrument out of your visual field within the abdomen can become a liability if it contacts an unintended organ. Communication between the laparoscopist and the camera operator is paramount. Training prior to surgery is key to efficient operating time and patient outcome in the operating room. A study from 2014 showed that on average it took a surgeon ~80 laparoscopic ovariectomies to become “proficient” at the procedure.6 Proficiency was defined as a reduction in complications. Minimally invasive training in the veterinary field has historically been absent in veterinary schools with the exception of surgery residencies. This stems from the shift away from working with research animals, the limited availability and “shelf life” of 21 cadavers, and funding. In human medical surgery residencies, there is now a requirement for simulator based laparoscopic surgery training which has been shown to translate into proficiency in the operating room. Research is being performed in veterinary training with simulators which mirrors these results. Like any task, practice helps fine tune the fundamental skills associated with completing it. Training simulators are a great way to obtain practice. This varies from box simulators (mass produced and homemade), virtual reality, and augmented reality (hybrid VR). An example of an inexpensive homemade box trainer uses a plastic tote container with a laptop placed on top. A webcam connected via USB adapter is mounted within the box trainer and instrument ports are placed through the top of the box to execute exercises inside the box. Common core exercises include peg transfer, pattern cutting, ligature loop placement, extra- and intracorporeal knot tying.2 Variable simulators exist in academic settings that can range in cost up to $90,000. Multiple studies have shown that human and veterinary surgeons who play and/or train with recreational video games are the fastest to adopt laparoscopic surgical skills.7-13 Formal training programs for veterinarians are offered through Colorado State University as well as University of Georgia and range from $1700-2000. These are set up as basic and advanced courses. Additional courses for surgery residents and veterinary surgeons are available at the annual ACVS meetings. Equipment The most basic laparoscopy set up includes a light source, light-transmitting cable, endoscope, camera, and monitor. A carbon dioxide insufflator is also essential for most laparoscopy. With thoracoscopy, insufflation is not necessary and can actually be harmful from a cardiovascular standpoint. Because of the added equipment, a larger operating room is often necessary for minimally invasive surgery (MIS). Keep in mind that there is the need for a laparoscopy tower, anesthesia tower, operating table with room for long instruments, and room for the surgeon and assistant to move about the room. An HD laparoscopy tower with insufflator and basic instruments can approach $100,000 in cost however there are refurbished and used towers that can be acquired through multiple resources for a considerable discount. More compact systems (Telepak Vet X LED, Storz) exist that incorporate the light source, monitor, computer, and insufflator into one compact package which ends up costing approximately $50,000 but has different quality compared to the HD systems (Information provided through correspondence with Storz representative). A recent prospective study14 showed that introduction of rigid laparoscopy into a general practice can be feasible and lucrative. An entry level laparoscopy pack should include a 5mm 0-degree telescope, a light cable, insufflator tubing, endoscopic video camera, a Veress needle (if desired for pneumoperitoneum creation), three 5-mm cannulas with two sharp trochars and one blunt-tipped trochar, one to two 10-mm cannulas with one sharp and one blunt trochar, two reducer caps (from 10mm to 5mm), 10-mm double action Babcock forceps, 5-mm double action babcock forceps, two 5-mm Kelly or Maryland grasping forceps, 5-mm Metzenbaum scissors, 5-mm cup biopsy forceps, 5-mm punch biopsy forceps, a 5-mm palpation/measurement probe, and an ovariectomy hook.2 For more advanced surgeons, right angled dissecting forceps, needle drivers (two pairs), a fan retractor, a 5-mm 30-degree telescope, bipolar vessel sealing equipment (ligasure, Covidien Medtronic, MN), miniature equipment and telescope (3mm), and single-port access equipment and instruments can be added. Additional equipment that can be helpful are specimen retrieval bags, suction/irrigation equipment and wound retractors for lap-assisted surgery. Laparoscopic clip applicators and stapling devices are extremely helpful for advanced procedures like cholecystectomies, nephrectomies, and lung lobectomies. 22 Complications During laparoscopy, it is important for the anesthetists to remain aware of the patient status as pneumoperitoneum is established and maintained. By insufflating the abdomen to 10-15mmHg, hepatic, renal, and mesenteric blood flow is decreased. Between 16-20mmHg, portal venous, mesenteric, and celiac venous blood flow is decreased. Above 20mmHg, renal blood flow and GFR decrease by greater than 75% and anuria occurs.2 It is important to maintain as low of pneumoperitoneum pressure as possible during sustained surgeries. I typically aim for 7-10mmHg. Cats are especially susceptible to the hemodynamic effects of pneumoperitoneum. Case et al. showed that with even low pressure pneumoperitoneum (6mmHg) there was significant rise in venous partial pressure of CO2 (PvCO2) and heart rate with a concurrent decrease in stroke volume while maintaining cardiac output.15 These signs were worsened with the duration of the procedure but resolved with completion of the surgery. Based on this information, cats should be operated on when a laparoscopist is proficient with canine patients who are more accommodating to the effects of pneumoperitoneum. In humans, low pressure pneumoperitoneum reduces the incidence of postoperative “shoulder-tip” pain which we have not yet recognized in veterinary patients.16 Shoulder-tip pain (Kehr's sign) is a classic example of referred pain wherein irritation of the diaphragm during pneumoperitoneum is signaled by the phrenic nerve as pain in the area above the collarbone. This is because the supraclavicular nerves have the same cervical nerves origin as the phrenic nerve, C3 and C4. Patient positioning with head down (Trendelenberg positioning) or head up (reverse Trendelenberg or Fowler positioning) can also lead to respiratory and hemodynamic compromise. The pertinent risks of laparoscopic surgery include vascular and visceral injury. The rate of vascular injury is low but something that should always be discussed with owners prior to surgery. Vascular injury risk is the highest upon initial entry into the abdomen. The risk of vascular injury is slightly higher for a closed technique (Veress and direct trochar insertion) at 0.04% versus an open (Hasson) technique at 0.01%. 17 Indications to convert include hemorrhage that cannot be corrected laparoscopically, hemodynamic compromise in the face of hemorrhage, or progressive retroperitoneal hemorrhage. Visceral injuries can occur with either technique however with the open technique, the problem is often immediately identified and can be corrected. History of previous abdominal surgery makes the likelihood of adhesions higher and thus a greater risk for inadvertent visceral injury. Injuries to the small bowel or large bowel need to be corrected while injuries to the stomach can often be treated conservatively. Thermal burns can occur with any electrosurgical equipment but is highest with monopolar equipment. Examples of burns include direct coupling (contact with unwanted tissue leading to burn), indirect coupling (leaking in an insulation barrier allows energy to escape and contact tissue), and capacitive coupling (build-up of energy between two conducting substances separated by an insulating substance. This is most common with hybrid plastic/metal cannulas and can be reduced with full plastic or full metal cannulas). Thermal injuries are often not identified at the time of initial surgery and show up later postoperatively as flank bruising or burns. 23 Relative anatomic contraindications for MIS surgery (Adopted from Frannson et al.) Obesity Reoperative abdomen or thorax (Adhesions) Aberrant anatomy Cirrhosis, portal hypertension (vascular varicosities) Small bowel obstruction (decreased working space with dilated bowel) Septic peritonitis (inability to find source as well as increased risk of bacterial translocation into circulation with insufflation Disseminated abdominal cancer (port site metastasis extremely rare) Relative physiologic contraindications for MIS surgery (Adopted from Frannson et al.) Pulmonary disease (hypercarbia and hypoventilation) Cardiovascular disease (decreased pre-load and cardiac output with insufflation) Intracranial disease Coagulopathy Pregnancy Shock Procedures Diagnostic laparoscopy of the GI tract (beginner to intermediate) ● Typically performed in a combination of laparoscopy and lap-assisted techniques ● The gastric antrum, caudal duodenal flexure, and ileocecocolic junction are difficult to evaluate externally due to their deep attachments therefore they are typically visualized and palpated laparoscopically ● The small intestines can be exteriorized through a wound retractor (Alexis, Allied Medical) and explored manually by palpation in a hand-over-hand technique Laparoscopic-assisted gastrotomy, enterotomy, enterectomy, and anasatamosis (beginner to advanced) ● Very helpful to have an array of different sized radial wound retractors (Alexis, Applied Medical) ● Section of bowel is extFeriorized or brought to the body wall surface with stay sutures ● Surgery is performed outside of the body wall Laparoscopic-assisted gastrostomy or enterostomy tube placement (beginner) ● The respective segment of the GI tract is grasped under laparoscopic guidance and pulled to the body wall (2 port technique) ● The port with the instrument grasping the bowel is extended into a mini-laparotomy is performed and the feeding tube is placed through a stab incision in the affected segment of bowel ● A purse string and four-quadrant pexy is performed to secure the segment of the GI tract to the body wall Laparoscopic or laparoscopic-assisted gastropexy (intermediate) ● For total laparoscopic gastropexy, two laparoscopic needle drivers are necessary ● Barbed suture (V-Loc or Quill) makes the total laparoscopic procedure much easier because extracorporeal knots are not required and the suture maintains tissue apposition when tightened ● Total laparoscopic is more technically demanding but has a more cosmetic outcome ● Lap-assisted gastropexy often leads to a transient seroma in the paramedian incision site 24 Laparoscopic and laparoscopic-assisted splenectomy (intermediate) ● Important case selection (no peritoneal effusion, masses less than 6cm in diameter, no massive splenomegaly) ● Reported risk includes hemorrhage with manipulation of the spleen ● Complication rate reported at 15.5% for laparoscopic splenectomy compared to 26.6% in traditional open splenectomy based on large meta-analysis Liver biopsy and cholecystocentesis (beginner) ● Can be performed through a single-port technique (SILS or 10mm operating scope) or multiport ● Very low complication rate even in patients with coagulopathy or ascites ● Biopsy quality is excellent Laparoscopic cholecystectomy (intermediate to advanced) ● Low complication rate with appropriate case selection ● Cases with no elevation in total bilirubin ● In humans, intraoperative cholangiograms are performed under fluoroscopic guidance which allows flushing of the common bile duct and proving patency in bilirubinemic patients (stay tuned for veterinary medicine) ● Check coagulation status ● A clip applicator makes the procedure easier and negates the need for extracorporeal knot tying ● Vessel sealing device has not been verified for use on the cystic duct Laparoscopic adrenalectomy (intermediate to advanced) ● A vessel sealing device is highly recommended ● Low complication rate with appropriate case selection ● Invasion into phrenicoabdominal vein is okay; caval invasion is contraindicated. ● No difference in risk for postoperative thromboembolism ● Reduces risks associated with hyperadrenocorticism and delayed wound healing Laparoscopic renal biopsy (intermediate) ● Indications include progressive proteinuria or acute kidney injury of an unknown cause ● Chronic severe kidney disease will likely not benefit from a renal biopsy as the progression is predictable ● Other contraindications include uncontrolled systemic hypertension, hydronephrosis, uncontrolled pyelonephritis, cystic renal disease, coagulopathy ● Biopsies obtained from renal cortex only to avoid bleeding ● Biopsies should be analyzed by light, immunofluorescence, and electron microscopy by an experienced nephropathologist ● In general, this is a safe procedure when performed laparoscopically however patients should be monitored for postoperative hemorrhage Laparoscopic ureteronephrectomy (advanced) ● Indications include primary renal neoplasia, hydronephrosis, chronic renal infection, renal dysplasia, nephrolithiasis, and idiopathic renal hematuria ● Ideally assessment of the GFR of the contralateral kidney is warranted before removal (scintigraphy or contrast-enhanced CT) ● This is an advanced procedure for doctors with extensive open nephrectomy experience as well as extensive laparoscopy experience ● A vessel sealing device or clip applicator is highly desired for this procedure 25 Laparoscopic-assisted cystoscopy and “percutaneous cystolithotomy” (intermediate) ● Indicated for urolith removal as well as polyp removal ● Preferred technique for pediatric humans since transurethral removal is not possible with small urethral diameter ● Contraindications to this technique are large stones that would require a larger incision to be made in general ● Complete stone removal in 96% of cases due to direct visualization and dilation of mucosal folds whereas traditional cystotomy leads to 10-20% retained stones18,19 Laparoscopic ovariectomy, ovariohysterectomy, hysterectomy (beginner to intermediate) ● Ovariectomy is just as effective at sterilization as OHE ● Vessel sealing device is highly desirable for this procedure ● Single- versus multi-port techniques exist ● Tilt tables are useful ● OHE can be performed safely for mild uterine horn pathology (mucometra and pyometra) ● Hysterectomy can be performed in a lap-assisted technique to retain ovary if desired Cryptorchidectomy and vasectomy (beginner) ● Highly effective as a laparoscopic technique ● Single- or multi-port technique exist ● Vessel sealing device is highly desired for this procedure ● Palpation of the inguinal region prior to surgery is recommended ● The inguinal ring is visualized at the time of surgery (visualization of a single structure (gubernaculum) confirms abdominal cryptorchid; visualization of two structures (ductus deferens and testicular artery/vein) confirms that the testicle has completed migration into the inguinal canal and conversion to inguinal approach is typically necessary ● Vasectomy involves sealing and dividing the ductus deferens as it exits the inguinal canal ● Can be performed at the time of and in combination with other procedures (gastropexy) Diaphragmatic and inguinal herniorrhaphy (advanced) ● Useful for acute diaphragmatic hernias ● Low pressure (3mmHg) insufflation utilized due to open thoracic cavity ● Barbed suture is highly desired as well as laparoscopic needle drivers ● Liver and spleen can be the most difficult organs to reduce ● May need to combine thoracoscopic and abdominal laparoscopy to both push and pull simultaneously 26 References 1. Mishra, RK. Chronological advances in minimal access surgery. Textbook of Practical Laparoscopic Surgery. 2 nd ed. Jaypee Brothers Medical Publishers pp 3-8. 2. Frannson BA, Mayhew PD. Small Animal Laparoscopy and Thoracoscopy. Wiley Blackwell. 3. Hancock RB, Lanz OI, Waldron DR, et al. Comparison of Postoperative Pain After Ovariohysterectomy by Harmonic ScalpelAssisted Laparoscopy Compared with Median Celiotomy and Ligation in Dogs. Veterinary Surgery 2005;34(3):273-282. 4. Devitt CM, Cox RE, Hailey JJ. Duration, complications, stress, and pain of open ovariohysterectomy versus a simple method of laparoscopic assisted ovariohysterectomy in dogs. JAVMA 2005; 227(6):921-927. 5. Gauthier O, Holopherne-Doran D, Gendarme T, et al. Assessment of postoperative pain in cats after ovariectomy by laparoscopy, median celiotomy, or flank laparotomy. Vet Surgery 2015;44:O23-O30. 6. Pope JFA, Knowles TG. Retrospective Analysis of the Learning Curve Associated with Laparoscopic Ovariectomy in Dogs and Associated Perioperative Complication Rates. Vet Surgery 2014; 43:668-677. 7. Badurdeen S, Abdul-Samad O, Story G, et al. Nintendo Wii video-gaming ability predicts laparoscopic skill. Surgical Endoscopy 2010; 24(8):1824-1828. 8. Boyle E, Kennedy AM, Traynor O, et al. Training surgical skills using nonsurgical tasks- can Nintendo Wii improve surgical performance? Journal Surgery Education 2011;68(2)148-154. 9. Adams BJ, Margaron F, Kaplan BJ. Comparing video games and laparoscopic simulators in the development of laparoscopic skills in surgical residents. Journal Surgery Education 2012;69(6):717-717. 10. Grantcharov TP, Funch-Jensen P. Can everyone achieve proficiency with the laparoscopic technique? Learning curve patterns in technical skills acquisition. American Journal of Surgery 2009;197(4):447-449. 11. Shane MD, Pettitt BJ, Morgenthal CB, et al. Should surgical novices trade their retractors for joy-sticks? Videogame experiences decrease the time needed to acquire surgical skills. Surg Endosc 2008;22(5):1294-1297. 12. Towle Millard HAMR, Freeman LJ. Association between Wii video gaming ability, 3-D spatial analysis skills, and laparoscopic performance and the level of surgical interest and gender in third year veterinary students. Presented at the 11 th Annual Scientific Meeting of the Veterinary Endoscopy Society. Florence, Italy, May 15-17 2014. 13. Rosser JC, Lynch PJ, Cuddihy L, et al. The impact of video games on training surgeons in the 21 st century. Arch Surg 2007;142(2):181-186. 14. Jones K, Case JB, Evans B, et al. Evaluation of the economic and clinical feasibility of introducing rigid endoscopy and laparoscopy to a small animal general practice. JAVMA 2017;250(7):795-800. 15. Shih AC, Case JB, Coisman JG, et al. Cardipulmonary Effects of Laparoscopic Ovariectomy of Variable Duration in Cats. Vet Surgery 2015;44:O2-O6. 16. Sarli L, Costi R, Sansebastiano G, et al. Prospective randomized trial of low-pressure pneumoperitoneum for reduction of shoulder-tip pain following laparoscopy. British Journal of Surgery 2000; 87(9): 1161-1165. 17. Malloy D, Kaloo PD, Cooper M, et al. Laparoscopic entry: a literature review and analysis of techniques and complications of primary port entry. Aus N Z J Obstetrics Gynaecology 2002; 42(3):246-254. 18. Lulich JP, Osborn CA, Thumchai R, et al. Management of canine calcium oxalate urolith recurrence. Compendium Continuing Education Practice 1998; 20(2):178. 19. Grant DC, Harper TAM, Werre SR. Frequency of incomplete urolith removal, complications, and diagnostics imaging following cystotomy for removal of uroliths from the lower urinary tract in dogs: 128 cases (1994-2006). JAVMA 236(7):736766. 20. Walsh PJ, Remedios AM, Ferguson JF, et al. Thoracoscopic Versus Open Partial Pericardiectomy in Dogs: Comparison of Postoperative Pain and Morbidity. Veterinary Surgery 1999;28(6):472-479. 21. Buoute NJ. Client and referring veterinarian perceptions about laparoscopy in an urban setting. Presented at the 13 th Annual Scientific Meeting of the Veterinary Endoscopy Society. Jackson Hole, Wyoming, June 2016. 27 Cell-based model of coagulation: a thromboelastographic analysis Seung Yoo MS MBA DVM DACVP (Clinical Pathology) Seattle Veterinary Specialists – BluePearl Kirkland, WA Overview of hemostasis Hemostasis is an essential protective process that acts to prevent blood loss by providing a mechanical seal on the vascular system. This process involves a complex and dynamic response that results in a thrombus. Under normal physiologic conditions, there are many known (and likely unknown) well-regulated mechanisms that regulate this thrombus formation and its eventual dissolution. Both cellular and protein components participate in an interlinked meshwork of relationships that can ultimately result in a phenotype between uncontrolled bleeding and pathologic thrombosis. A thorough understanding of these relationships is vital to anticipating the clinical consequences that can occur due to dysfunction of these pathways. A list of key molecules for hemostasis is provided in Table 1. Blood needs to flow Vascular endothelium plays many roles besides merely acting as a physical barrier between blood and extravascular tissues. Endothelium plays a critical role in coagulation and fibrinolysis, regulating blood pressure with vasodilation and vasoconstriction, leukocyte translocation and thus inflammation, and lipoprotein trafficking. Undisrupted vascular endothelium is naturally anti-coagulant. There are numerous anticoagulants that prevent or delay uncontrolled thrombus formation. Heparan sulfate glycosaminoglycans (HSPGs) are expressed by endothelial cells. These large molecules contain a neutral membrane charge which is unable to support coagulation reactions. Antithrombin (AT) is bound to endothelial cells via interactions with these surface heparans. This complex inhibits several circulating coagulation factors in both the intrinsic and extrinsic pathways. Free AT has very weak inhibitory effects on the coagulation factors. This molecular interaction is the pharmacologic basis for anti-coagulant heparin therapy. Tissue factor pathway inhibitor (TFPI) is the key regulator of the extrinsic pathway. Endothelium expresses tissue factor pathway inhibitor (TFPI) which prevents thrombin generation by inhibiting factor Xa and TF-FVIIa complex. Endothelial cells also express nitric oxide, adenosine diphosphatase (ADPase), and PGI2 (prostacyclin) in response to several stimuli. All three molecules inhibit platelet activation with nitric oxide and PGI2 resulting in vascular relaxation. Thrombomodulin is also expressed by intact vascular endothelium. Thrombomodulin binds to thrombin and limits coagulation by both deactivating this molecule and by activating other anticoagulant molecules such as protein C and TFPI. Thus, any circulating thrombin is rapidly deactivated by endothelial bound thrombomodulin, localizing thrombin activity to vascular damage. Blood flow needs to cease Primary hemostasis - Upon disruption of the endothelial barrier, vWF is released which plays a key role in mediating platelet adherence via interaction with the platelet receptor Gp1b. vWF binds to subendothelial collagen and activates bound platelets. During subsequent platelet activation, platelet aggregation mediators 28 such as thromboxane (TXA2) and adenosine diphosphate (ADP) further activate nearby platelets leading to the beginning of a platelet plug. Once activated, platelets also express functional fibrinogen receptors that are derived from the platelet integrin glycoprotein IIbIIIa receptor. This results in further interplatelet binding and aggregation resulting in a relatively weak physical barrier to blood loss. Secondary hemostasis (Figure 1) - After endothelial injury, tissue factor (TF) is exposed on subendothelial collagen, activating the extrinsic coagulation pathway. TF binds to FVII, activating this pathway. FVIIa activates FX to FXa which subsequently leads to formation of thrombin FIIa. FIIa then catalyzes the reaction from fibrinogen to fibrin. In the traditional cascade model of coagulation, the intrinsic pathway can also lead to formation of fibrin. The formation of FXIIa on activated platelet surfaces initiates the intrinsic pathway. FXIIa promotes the formation of FXIa which subsequently promotes the formation of FIXa. FIXa binds with FVIIIa to form the FIXa-FVIIIa enzyme complex, also referred to as ‘tenase’ due to its substrate, FX. FXa binds with FVa to form the prothrombinase complex, which catalyzes the formation of thrombin (FIIa) from prothrombin (FII). Thrombin then cleaves fibrinogen to form fibrin, forming the intercellular ‘glue’ that meshes the platelets together within the platelet aggregate. This results in a stronger physical barrier to blood loss. Thrombin also catalyzes the formation of FXIIIa from FXIII. After fibrin is polymerized into an insoluble dimer, crosslinking forms lateral bonds, strengthening the fibrin meshwork. FXIIIa promotes this crosslinking, forming a stable clot. Figure 1: Traditional cascade model of hemostasis Blood needs to flow again After clot formation, blood flow must be restored by fibrinolysis. Fibrinolysis is mediated by several activators, inhibitors, and receptors, all of which have controlled roles. Plasminogen is a pro-enzyme that circulates in plasma which is a precursor to plasmin. Plasminogen is enzymatically cleaved into plasmin by tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). It is thought that tPA is the primary plasminogen activator within the vasculature and uPA is the primary plasminogen activator within extravascular tissue. Plasmin then cleaves fibrin to form fibrin degradation products, including D-dimers. Just as clot 29 formation is carefully controlled, fibrinolysis is primarily controlled by plasminogen activator inhibitor 1 (PAI-1). PAI-1 binds to tPA and uPA, preventing their actions. α2-antiplasmin binds to plasminogen, preventing its interaction with fibrin, thus preventing fibrinolysis. Thrombin activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by removing binding sites for plasminogen and its activators, tPA and uPA. The cell based model of hemostasis The development of the cell based model of coagulation was prompted by recognized deficiencies in the traditional cascade model of coagulation. For example, some mammalian species (whales, dolphins) do not express FXII which raises some doubt about the absolute necessity of this factor. Also, deficiencies in FXII are not associated with bleeding in mice or humans, despite a significant prolongation in APTT time. Another example highlighting the insufficiencies of the cascade model is hemophilia. Deficiencies of either FVIII (hemophilia A) or FIX (hemophilia B) will result in moderate to severe bleeding despite the presence of an intact extrinsic pathway. Hemophilia C (FXI deficiency) will result in variable bleeding in humans. Lack of FVII is associated with mild to moderate bleeding despite the presence of an intact intrinsic pathway. While the cascade model of coagulation may be useful for understanding the kinetics and enzyme interactions during hemostasis in vitro, it is evident that this model is incomplete in describing the process of coagulation as it occurs in vivo. Instead of considering the intrinsic and extrinsic pathways as separate redundant pathways that interact independently with the common pathway, all three pathways are necessary for functional coagulation to occur. The cell based model of hemostasis proposes two primary changes in evaluating coagulation: 1) tissue factor is the primary physiologic activator of coagulation in vivo, and 2) coagulation requires cell surfaces for regulation and localization. The following figures (2-4) diagrams the cell surface interactions of key players leading up to fibrin formation. The cell based model of hemostasis is based upon three interacting phases, initiation, amplification, and propogation. Inititation After vascular injury, TF is exposed on cells that generally reside in the extravascular space (Figure 2). Circulating FVIIa binds to TF and this complex promotes the formation of more TF-FVIIa complex which, in turn, promotes the formation of prothrombinase complex (Xa-Va). The subsequent small scale production of thrombin activates localized platelets. Any FXa that is released from the cell surface is deactivated by circulating TFPI or AT, limiting this process to TF at the cell surface. FIXa is also produced by TF-FVIIa complex. Figure 2: Initiation 30 Amplification Vascular wall damage also exposes sites for platelet adhesion (not pictured). Thrombin binding to these platelets results in activated platelets, leading to conformational changes and release of granule contents, further promoting the process of coagulation (Figure 3). Thrombin also activates surface bound FXI and FV to their active forms. Circulating vWF-FVIII complexes are cleaved by thrombin, releasing vWF that promotes platelet to platelet adhesion and further aggregation. The released FVIII is also activated by thrombin. After platelet activation and production of FVa, FXIa, FVIIIa, and assembly of procoagulant complexes, thrombin can be produced en masse. Figure 3: Amplification Propagation FIXa, FXa, and FXIa have high affinity binding sites on platelets where it is thought that the following reactions take place (Figure 4). FVIIIa-FIXa complex (tenase) and FXa-FVa complex (prothrombinase) assemble on the platelet surface leading to large scale thrombin production. FVIIIa-FIXa complexes activate surface bound FX where the resulting FXa can move into a complex with its cofactor FVa to produce the ‘thrombin burst’ that is needed to form an effective fibrin clot. Circulating and platelet released fibrinogen is cleaved by thrombin to form fibrin monomers that spontaneously polymerize to form fibrin polymers. 31 Figure 4: Propogation This model explains the bleeding tendencies from deficiencies in FVIII, FIX, and FXI as these factors are required for the generation of FXa, and subsequent production of thrombin, on TF bearing cell surfaces and platelet surfaces. A better understanding of hemostasis using this model instead of the traditional cascade model has spurred the development and use of viscoelastic point of care devices. Viscoelastic devices provide in vitro evaluation of global coagulation in a whole blood sample, including the beginning of clot formation to fibrinolysis. These devices are considered a better method of evaluating hemostasis with the interaction of all cellular and clotting factor interactions in whole blood compared to conventional coagulation assays. The time to clot formation, rate of formation, clot strength, and clot stability can be evaluated, providing information on the ability of the clot to provide hemostasis. In human medicine, TEG is used to provide valuable guidance during organ transplantation surgeries, cardiopulmonary bypass, and trauma assessment. These instruments allow for monitoring of the different phases of hemostasis so that specific administration of drugs or blood products can be used to address the primary hemostatic dysfunction, potentially decreasing costs and morbidity/mortality. There are three primary viscoelastic techniques: thromboelastograph (TEG), rotational thromboelastometry (ROTEM), and Sonoclot. These techniques use different methods of measuring hemostasis and should not be used interchangeably. However, all three methods can measure speed and strength of clot formation and fibrinolysis. For the purposes of this article, only TEG will be discussed. TEG evaluates the physical properties of a clot under low shear conditions using a cup that holds a blood sample while rotating through a small angle (Figure 5). A pin is suspended from a torsion wire within the blood-filled sample cup. When clotting occurs, the formation of fibrin and platelet aggregates between the pin and walls of the cup causes movement of this pin. This movement is converted by a transducer into an electrical signal that is translated into a graphical output over time. Typically, whole blood is used but modified plasma based TEG 32 has also been evaluated. The procedure can be performed with fresh whole blood with or without anticoagulant sodium citrated blood. If performed with anticoagulant, a standard amount of CaCl 2 is added to the sample to initiate the coagulation process. Samples can be run with or without activation. Kaolin or celite can be used to activate the intrinsic pathway and tissue factor is typically used to activate the extrinsic pathway for a more rapid analysis. Figure 5 In veterinary medicine, TEG is utilized mostly in research settings although there are anecdotal reports of promise in clinical applications. TEG has been used to monitor hemostasis in dogs with IMHA, parvovirus infections, hyperadrenocorticism, and cancer. One of the main advantages of TEG is the ability to monitor hypercoagulability, whereas most other traditional tests for coagulation only test for hypocoagulability. However, there are no reports of using TEG to predict thrombosis. It is important to understand that hypercoagulability as shown by TEG does not necessarily indicate pathologic dysfunction of the hemostatic system. The degree of hypercoagulability has not been shown to correlate with risk of thrombosis. In fact, there is some evidence that suggests that lack of hypercoagulability may be associated with thrombosis. There has been an increase in recent research for utilizing TEG to monitor hemostasis with acute trauma, critical illness associated coagulopathy, and anticoagulant drug therapy. There is much potential for future clinical research as an improved understanding of hemostasis with the incorporation of cellular components will give us better tools for diagnosis and treatment of hemostatic dysfunction. As the tests become more standardized and equipment costs decrease, clinical application may become more common. 33 TEG parameters A TEG tracing (Figure 6) provides an abundant of both qualitative and quantitative data. The commonly used parameters are: R (min) – value over time from the beginning of the tracing until the amplitude of deflection is 2 mm. This value provides the time elapsed from the initiation of the run until clot formation begins. This value is influenced by the coagulation factors in the extrinsic, intrinsic, and common pathways. K (min) – the time from the end of R until the amplitude is 20 mm apart. This somewhat arbitrary value signifies a standard level of clot firmness. K is influenced by the coagulation factors in the extrinsic, intrinsic, and common pathways. This value is also influenced by platelet count and function, fibrinogen/fibrin, and hematocrit. α (degrees) – the angle formed with a tangential line starting from the end of R to the TEG tracing. This angle is influenced by the same components as K; the coagulation factors in the extrinsic, intrinsic, and common pathways. This value is also influenced by platelet count and function, fibrinogen/fibrin, and hematocrit. MA (mm) – this is maximum distance between the two arms of the tracing. MA represents the maximum strength of the clot. It is influenced by fibrinogen/fibrin, platelet count and function, thrombin, FXIII, and hematocrit. Figure 6: TEG tracing CI (coagulation index) – given by the formula derived from a combination of all the above parameters. CI = 0.1227(R) + 0.0092(K) + 0.1655(MA) – 0.0241(α) – 5.0220 A normal CI value ranges from -4.0 to 4.0. With values less than -4.0 representing a hypocoagulable state and values greater than 4.0 representing a hypercoagulable state. This equation simplifies interpretation of coagulation status but we lose the ability to evaluate the individual components of the tracing. LY30, LY60 – this value denotes the percent decrease of the TEG tracing from MA from 30 or 60 minutes respectively. This value represents rate of fibrinolysis. 34 G (dynes/sec) – this value is calculated from MA using the formula G=5000 x MA/(100-MA). This value is thought to better represent the physical strength of the clot as this value increases exponentially with increased MA. Other parameters that are used less frequently include the following (Figure 7): MRTG (dynes/cm2/s) – maximum rate of thrombin generation is determined from the first derivative of the TEG curve. This corresponds to the steepest portion of the TEG tracing. TMRTG (min) – time to maximum rate of thrombin generation is defined as the time interval observed prior to maximum speed of clot growth. TTG (dynes/cm2) – total thrombin generation is defined as the total area under the velocity curve during clot formation. Figure 7: Elastic modulus tracing in green Extrinsic pathway TF FVII Tissue Factor Factor VII Intrinsic pathway FXII Factor XII FXII FIX FVII I Common pathway FX FV Pro Fg Fb FXIII Factor XI Factor IX Fibrinolysi s promoters Fibrinolysi s inhibitors Factor VIII Factor X Factor V Prothrombin Fibrinogen Fibrin Factor XIII Anticoagulant PLG PLM uPA tPA Plasminogen Plasmin Urokinase plasminogen activator Tissue-type plasminogen activator α2AP PAI-1 TAFI α2-antiplasmin Plasminogen activator inhibitor-1 Thrombin activatable fibrinolysis inhibitor AT TFPI PC PS TM PZ Antithrombin Tissue factor pathway inhibitor Protein C Protein S Thrombomodulin Protein Z Table 1: Key molecules for hemostasis 35 Suggested readings Abelson, A.L., O’Toole, T.E., Johnston, A., Respess, M., and de Laforcade, A.M. (2013). Hypoperfusion and acute traumatic coagulopathy in severely traumatized canine patients: Coagulopathy and severe trauma. Journal of Veterinary Emergency and Critical Care 23, 395–401. Brainard, B.M., Goggs, R., Mendez-Angulo, J.L., Mudge, M.C., Ralph, A.G., and Wiinberg, B. (2014). Systematic evaluation of evidence on veterinary viscoelastic testing Part 5: Nonstandard assays: PROVETS-Nonstandard assays. Journal of Veterinary Emergency and Critical Care 24, 57–62. Flatland, B., Koenigshof, A.M., Rozanski, E.A., Goggs, R., and Wiinberg, B. (2014). Systematic evaluation of evidence on veterinary viscoelastic testing Part 2: Sample acquisition and handling: PROVETS - Sample handling. Journal of Veterinary Emergency and Critical Care 24, 30–36. Hanel, R.M., Chan, D.L., Conner, B., Gauthier, V., Holowaychuk, M., Istvan, S., Walker, J.M., Wood, D., Goggs, R., and Wiinberg, B. (2014). Systematic evaluation of evidence on veterinary viscoelastic testing Part 4: Definitions and data reporting: PROVETS-Definitions and data reporting. Journal of Veterinary Emergency and Critical Care 24, 47–56. de Laforcade, A., Goggs, R., and Wiinberg, B. (2014). Systematic evaluation of evidence on veterinary viscoelastic testing Part 3: Assay activation and test protocol: PROVETS-Activation and test protocol. Journal of Veterinary Emergency and Critical Care 24, 37–46. McMichael, M. (2012). New Models of Hemostasis. Topics in Companion Animal Medicine 27, 40–45. McMichael, M.A., and Smith, S.A. (2011). Viscoelastic coagulation testing: technology, applications, and limitations: Viscoelastic coagulation testing. Veterinary Clinical Pathology 40, 140–153. McMichael, M., Goggs, R., Smith, S., Wagg, C., Warman, S., and Wiinberg, B. (2014). Systematic evaluation of evidence on veterinary viscoelastic testing Part 1: System comparability: PROVETS - System comparability. Journal of Veterinary Emergency and Critical Care 24, 23–29. Palmer, L., and Martin, L. (2014). Traumatic coagulopathy-Part 1: Pathophysiology and diagnosis: Traumatic coagulopathy: Part 1. Journal of Veterinary Emergency and Critical Care 24, 63–74. Smith, S.A. (2009). The cell-based model of coagulation. Journal of Veterinary Emergency and Critical Care 19, 3–10. 36 Ureteral Obstructions: Diagnosis and Treatment Options Danielle Pollio, DVM (Practice Limited to Emergency and Critical Care) Seattle Veterinary Specialists Kirkland, WA Common presentations Cats with ureteral obstruction typically present with non-specific signs (vomiting, lethargy, hiding, decreased appetite, and weight loss).1 More severe signs such as oral ulcerations, weakness and anorexia are not typically observed unless the patient is markedly azotemic. Signs of dysuria are not typically seen unless the patient has concurrent bladder/urethral stones or urinary tract infection. Pain on palpation of the affected kidney(s) may also be appreciated in patients with acute obstructions.1 Dogs with ureteral obstructions will often show signs of dysuria (incontinence, stranguria, hematuria, polyuria, pollakiuria) and systemic signs (vomiting, decreased appetite, lethargy).1 Causes of ureteral obstruction Ureteroliths Stricture Inflammation Neoplasia Iatrogenic (e.g. ligation of ureters) Trauma Diagnosis On physical examination, cats will commonly have one enlarged, sometimes painful kidney and one small kidney. In dogs, renal pain is more common, likely due to concurrent renal infection and inflammation.1 Pale mucus membranes and a heart murmur are also commonly identified in cats with ureteral obstruction. 1 Abnormal biochemical findings in cats include azotemia (83%), anemia (48%), hyperphosphatemia (54%), hyperkalemia (35%), hypocalcemia (22%) and hypercalcemia (14%).1 The degree of azotemia on presentation does not appear to be associated with outcome if successful decompression is achieved. 2 On urine analysis, crystals were documented in 29% of cats (amorphous and calcium oxalate crystals were most common). Approximately 33% of cats have concurrent urinary or kidney infections based on positive urine or stone culture.1 Over 98% of feline ureteroliths are composed of calcium oxalate; however, other stone types including dried solidified blood calculi and struvite stones have been reported.3,4 In dogs, common biochemical abnormalities include azotemia (50%), thrombocytopenia (44%), and moderate to severe neutrophilia.1 Approximately 77% of dogs also have concurrent pyelonephritis and cystitis based on positive urine or stone culture.1 The combination of abdominal radiographs and abdominal ultrasound is the preferred method of diagnosis for ureteral obstruction. Stone size, number, location and the presence of concurrent nephrolithiasis may be documented with radiographs, whereas this information can be underestimated with ultrasound. 1 Nonradiopaque calculi or the presence of fecal material in the colon can obscure visualization of the ureter and associated renal pelvis with abdominal radiographs.1 37 Ultrasound can be used to document hydroureter, hydronephrosis and help pinpoint the exact location of the obstructive lesion. Bilateral ureteral obstructions are seen in 19% of cats and 12.5% of dogs. 1 Approximately 62% of cats and 50% of dogs had concurrent nephroliths.1 Identification of concurrent uroliths and obtaining measurements of the renal pelvis help the clinician choose which treatment option is ideal for the patient. Percutaneous antegrade pyelography, retrograde ureteropyelopgraphy and computed tomography can also be used to help differentiate between partial or complete obstructions and may be used in cases with traditional surgical intervention.1 The measurement of glomerular filtration rate may assist in the decision to treat unilateral or bilateral obstructions or to perform a nephrectomy if absolutely indicated. 1 Medical management of ureteral obstructions Medical management should be started immediately after diagnosis of ureteral obstruction, as most patients are azotemic and also have concurrent chronic renal disease. Medical management alone has reported to be effective in 17% of cats in one study and there are no reports in dogs.1 Although there is a small rate of success, medical management should always be considered prior to more invasive interventions. Medical management consists of IV fluid therapy, mannitol CRI for patients without cardiac compromise (assessed via thoracic radiography, auscultation, and echocardiography), supportive medications (anti-emetics, antacid, and pain medication) and broad-spectrum antimicrobial therapy if indicated. Amitriptyline, prazosin, tamsulosin, verapamil and glucagon have been tried to promote ureteral smooth muscle relaxation and passage of calculi; however, these are all anecdotal reports and no studies have shown a benefit of one treatment over another for ureteral obstruction.1 The author’s preference is amitriptyline or prazosin (if no hypotension is present). If the patient is unstable, or medical management is not successful in 48-72 hours, additional interventions should be considered to avoid ongoing loss of renal function. Temporary interventions for ureteral obstruction may include nephrostomy tube placement (for external renal drainage, elimination of excessive hydrostatic pressure, and patient stabilization before a more permanent fixation), or dialysis (for patients with severe hyperkalemia or life-threatening fluid overload).1 Surgical management of ureteral obstructions Traditional surgical interventions for treatment of ureteral obstruction include ureterotomy, ureteral reimplantation, ureteronephrectomy and renal transplantation. Ureterotomy and ureteral reimplantation are the most commonly performed surgical techniques for treatment of ureteral obstructions in dogs and cats.1 Complications include edema at the surgical site, recurrence of ureteral obstruction from stones passing from the renal pelvis (occurred in 40% of cats in 1 study), stricture formation, and urine leakage from the surgery site.1 More than 10% of cats that survived surgical complications required a second surgical procedure during the same visit, and 30% of these patients were euthanized or died due to serial complications.1 Despite these complications, survival rates were higher with surgical management than with medical management alone. Ureteronephrectomy is a less complicated surgical procedure than ureteral reimplantation, but as more than 50% of cats and 40% of dogs remain azotemic after treatment for ureteral obstruction, this procedure is not recommended in order to preserve as much renal function as possible.1 38 Interventional management of ureteral obstructions Interventional methods for treatment of ureteral obstruction include nephrostomy tube placement, ureteral stenting, subcutaneous ureteral bypass placement, extracorporeal shock-wave lithotripsy (ESWL) and percutaneous nephroureterolithotomy (PCNUL). Nephrostomy tube placement requires fluoroscopy and ultrasound guidance and is typically a temporary procedure to allow external renal drainage, elimination of excessive hydrostatic pressure and patient stabilization before a more permanent procedure can be performed.1 Ureteral stenting has multiple benefits, including (1) bypass of ureteral obstruction, (2) passive ureteral dilation, (3) decreased surgical tension on the ureter after/during surgery, (4) aiding in extracorporeal shockwave lithotripsy and (5) prevention of migration of nephroliths that could result in future ureteral obstruction. 1 The main type of ureteral stent used in veterinary medicine is an indwelling double pigtail ureteral stent.1 This type of stent can remain in places for months to years if necessary and may be considered a longer-term treatment option (i.e. >4 years) for various causes of ureteral obstruction in dogs and cats.1 Intraoperative complications of ureteral stent placement include ureteral tear, ureterotomy leakage, renal pelvic rupture, advancement of the stent from the renal pelvis into the renal parenchyma and bladder stay suture site leakage.2,5 Anesthesia-related complications in cats included bradycardia (22%), hypotension (41%), and hypothermia (87%).6 Immediate post-operative complications associated with ureteral stent placement in cats include uroabdomen (8/117 cats in 1 study, 6/69 cats in another study) and subcutaneous leakage of urine around the nephrostomy tube.2,5 Short-term complications (<1 week) include dysuria (pollakiuria or stranguria), which was typically selflimiting in 7-10 days or resolved with a weaning dose of glucocorticoids.5,2 Nonurinary complications included congestive heart failure, pancreatitis, hepatic lipidosis and sepsis.5,2 Long-term complications (>1 month) included pollakiuria, stent migration, ureteritis, ureteral reobstruction, stricture, pyelonephritis, tissue in-growth on the stent, chronic mild hematuria, ureterovesicular reflux and urinary tract infections.1,7 Despite these complications, less than 10% of feline patients had serious adverse events from ureteral stent placement.1,5,2 Approximately 95% of cats had an improvement in serum creatinine after ureteral stent placement.1 Dogs have similar, but fewer reported complications than cats.1,5 Subcutaneous ureteral bypass (SUB) is used for treatment of feline ureteral obstruction when stent placement is not feasible or has failed.1 This is an indwelling device that uses a combination of locking-loop nephrostomy and cystotomy catheters, which are connected to a subcutaneous port. The device is placed with fluoroscopic and surgical assistance. Once implanted, the device can be accessed for sampling or flushing as needed. The port site is first clipped and prepared aseptically, then a Huber needle is used to penetrate the port. It is important that only a Huber needle be used as other needle types will damage the port and potentially cause device leakage. Ultrasound or fluoroscopy may be used to assess port patency. Cystocentesis should never be performed without ultrasound guidance and if indicated, should be done on the side opposite the SUB device. 1 Complications reported in the literature for SUB placement include leakage from nephrostomy site and port site and SUB occlusion.1,8 Additional complications include infection of the SUB device and hemorrhage. 1 Predictors significantly associated with a decreased overall survival for cats undergoing ureteral stent or SUB placement included presenting BUN, overhydration during hospitalization and creatinine value prior to hospital discharge.8 39 Extracorporeal shock-wave lithiotripsy (ESWL) delivers external shockwaves through a water medium directed under fluoroscopic guidance in 2 planes. The ureteral stone will implode and the powder debris is left to pass down the ureter into the bladder over 1-2 weeks.1 The procedure can be performed in ureteroliths <5 mm in dogs and <3-5 mm in cats.1 ESWL is not typically performed in cats because the fragments are rarely <1 mm and as the feline ureter is 0.3 to 0.4 mm in diameter this creates a high risk of ureteral obstruction.3 A ureteral stent may be placed prior to ESWL to aid in stone debris passage, imaging and immediate relief of ureteral obstruction.1 Percutaneous nephroureterolithotomy (PCNUL) is a procedure in which antegrade nephroureteroscopy is performed via renal access. If a stone is identified in the ureter, a stone basket can be used to remove the stone via the access sheath, or it can be broken with a laser lithotrite. 1 In feline patients this procedure is often performed with surgical assistance so kidney can be manually stabilized and the access point be closed primarily, avoiding the need for a temporary nephrostomy tube.3 Ureteroscopy is possible in large dogs (>20 kg). Ureteral access is gained via cystoscopy. A guidewire and flexible endoscope are used to assess the ureter. Once the cause of obstruction is identified, the proper management strategy (i.e. laser lithotripsy, balloon dilation for stricture) can be used to treat the problem. 1 Summary Many new options are now available for treatment of ureteral obstructions in dogs and cats. There are inherent risks with any surgical or interventional procedure, but with the proper patient selection, preparation, and postoperative care, these new modalities may provide significantly improved outcomes. References 1. Berent AC. Ureteral obstructions in dogs and cats: A review of traditional and new interventional diagnostic and therapeutic options. J Vet Emerg Crit Care. 2011;21(2):86-103. doi:10.1111/j.1476-4431.2011.00628.x. 2. Wormser C, Clarke DL, Aronson LR. Outcomes of ureteral surgery and ureteral stenting in cats: 117 cases (2006–2014). J Am Vet Med Assoc. 2016;248(5):518-525. doi:10.2460/javma.248.5.518. 3. Berent A. New techniques on the horizon: interventional radiology and interventional endoscopy of the urinary tract (’endourology’). J Feline Med Surg. 2014;16(1):51-65. doi:10.1177/1098612X13516572. 4. Palm CA, Culp WTN. Nephroureteral Obstructions: The Use of Stents and Ureteral Bypass Systems for Renal Decompression. Vet Clin North Am - Small Anim Pract. 2016;46(6):1183-1192. doi:10.1016/j.cvsm.2016.06.008. 5. Berent AC, Weisse CW, Todd K, Bagley DH. Technical and clinical outcomes of ureteral. J Am Vet Med Assoc. 2010;244(5):559-576. doi:10.2460/javma.244.5.559. 6. Garcia de Carellan Mateo A, Brodbelt D, Kulendra N, Alibhai H. Retrospective study of the perioperative management and complications of ureteral obstruction in 37 cats. Vet Anaesth Analg. 2015;42(6):570-579. doi:10.1111/vaa.12250. 7. Manassero M, Decambron A, Viateau V, et al. Indwelling double pigtail ureteral stent combined or not with surgery for feline ureterolithiasis: complications and outcome in 15 cases. J Feline Med Surg. 2014;16(8):623-630. doi:10.1177/1098612X13514423. 8. Horowitz C, Berent A, Weisse C, Langston C, Bagley D. Predictors of outcome for cats with ureteral obstructions after interventional management using ureteral stents or a subcutaneous ureteral bypass device. J Feline Med Surg. 2013;15(12):1052-1062. doi:10.1177/1098612X13489055. 40 Antifibrinolytics: A new therapy for bleeding Kelly Blackstock, MS, DVM, DACVECC Seattle Veterinary Specialists Kirkland, WA Before jumping into drugs that influence bleeding, it is important to have an understanding of the basics of coagulation and fibrinolysis. Traditionally, coagulation was taught in veterinary school as a “y” shaped model of numbers that cascaded down with the end result of the conversion of fibrinogen to fibrin. We know now that the endothelium is also a key player of this system, and that there is much more of a cell-based interaction among the factors, platelets and endothelium. The primary role of healthy endothelial cells is to prevent thrombus formation. They do so by inhibiting platelet activation via the secretion of nitric oxide (NO), prostacycline (PG-I2), and ADP-dephosphatases. They also contain binding surfaces for heparin sulfate and thrombomodulin, both of which inhibit activated clotting factors. Lastly, endothelial cells also secrete tissue plasminogen activator (t-PA), whose activation of plasminogen cleaves any formed fibrin. Should damage to the endothelial layer occur, the damaged cells secrete vonWillebrand factor, which leads to platelet adherence and activation. Once platelets are activated, secondary factors enter into the cell-based model of coagulation. The steps of this include initiation, amplification and propagation. The hallmark of the initiation phase is the generation of a small amount of thrombin. Thrombin formation further activates platelets, and factors, amplifying the substrates responsible for clot formation. The process is propagated by the amplified platelets and coagulation factors, leading to a burst of thrombin. The end result is an insoluble fibrin matrix known as a clot. The final phase of coagulation is the removal of the clot a process known as fibrinolysis. The basic mechanism of action for fibrinolysis involves the conversion of plasminogen to plasmin. Plasmin degrades fibrin into fibrin degradation products (FDPs) and D-dimers. Plasminogen can be activated by t-PA and urokinase plasminogen activator (u-PA). It can be inhibited by plasminogen activator inhibitor (PAI 1 and 2), thrombin activatable fibrinolysis inhibitor (TAFI), and α2-antiplasmin. Aminocaproic acid (EACA) and tranexamic acid (TEA) are synthetic lysine analogs. They are capable of inhibition of fibrinolysis by competitively binding to lysine-binding sites to reduce the conversion of plasminogen to plasmin. At higher doses they are also capable of direct inhibition of plasmin’s degradation of glycoprotein 1b receptors on platelets. This receptor is a key player for the initiation and amplification phase of coagulation. Historically, when presented with a patient with the complication of bleeding, the only treatment option available has been the transfusion of blood products. These therapies, while lifesaving are not without cost. Acquisition and storage of these products are expensive, and screening tests such as blood typing and crossmatch can increase the financial burden placed on an owner. Transfusion related complications are also well documented, ranging from mild acute hypersensitivity reactions, severe hemolytic or anaphylactic reactions1, immunosuppression, and transfusion-related lung injury (TRALI). In addition, recent studies have associated increased blood product administration and risk of mortality in critically ill people, a finding that was independent of severity of illness.2 For these reasons, having alternative options of therapy either in the prevention or improvement in bleeding might prove beneficial. Diagnosing problems with fibrinolysis is challenging, making identification of the patient populations at risk difficult. Hyperfibrinolysis is one of the hallmarks of acute traumatic coagulopathy (ATC). This syndrome is thought to be triggered by severe tissue injury, hypoperfusion and endothelial damage, leading to excessive activation of Protein C and disseminated intravascular coagulation (DIC).3 Although research is lacking with ATC 41 in animals, a recent case report documented hyperfibrinolysis in a dog following presumptive vehicular trauma. Likely for similar reasons, hyperfibrinolysis was found to be a component of coagulation abnormalities isolated in dogs with spontaneous hemoperitoneum.5 Hepatobiliary disease has also been associated with increased clot break down.6 Lastly, a subset of Greyhound dogs has been noted to bleed following surgical interventions. Investigation failed to show any differences in primary or secondary hemostasis 7, and treatment with EACA prevents this bleeding, suggesting that they, too, experience hyperfibrinolysis.8,9 The use of lysine analogs, EACA and TEA, has had documented benefit in people undergoing cardiovascular, pediatric, and orthopedic surgeries, dental procedures and trauma. 10 In a Cochrane review evaluating 3,836 people in 53 trials undergoing elective surgery, TEA administration lead to a reduction in the requirement for blood transfusions by a third as compared to controls.11 The CRASH-2 trial, a randomized placebo controlled prospective study, evaluated the use of TEA in 20,211 adult trauma patients at risk of significant bleeding. As compared to controls, patients who received TEA had a significantly lower all-cause mortality rate and bleedingassociated deaths. There is evidence that dogs are hyperfibrinolytic compared to humans. This was first observed in studies of pulmonary embolism in the 1960’s, in which experimentally induced emboli in dogs were found to resolve within hours to days, rather than the months to years typically seen in human patients. Ultimately, creation of a canine model of chronic pulmonary embolism was only possible after instituting treatment with TEA. 13,14 In addition, when therapeutic doses of EACA and TEA were specifically compared between humans and dogs in a TEG model of hyperfibrinolysis, dogs required much higher concentrations of both drugs to achieve the same level of effect.15 Increase in fibrinolysis in dogs is thought to be attributable to increased secretion of plasminogen activator by the pulmonary endothelium, increased plasminogen activator activity, and greater platelet thrombolytic activity.16 As dogs are believed to be hyperfibrinolytic, as compared to humans, it may stand to reason that they, too, may benefit from these drugs, perhaps even more so. As always the research on the veterinary side is limited, but interest is growing and the data is mounting. The first known publication for the use of EACA in dogs was a case series out of the Keio Journal of Medicine in 1959. In that report, oozing, created by activation of plasmin, from surgical incisions made in research dogs, was subjectively stopped quicker with the use of EACA.17 More recently EACA was evaluated in Greyhounds following surgical procedures. Lara-Garcia, et al., documented that roughly 30% of Greyhounds have been shown to have substantial bleeding roughly 36-48 hours following surgery for gonadectomy.18 In a prospective study evaluating EACA use in this population of dogs, post-operative bleeding was decreased by 20%.19 In another study looking at Greyhounds undergoing limb amputation, dogs that did not receive EACA were 5.7 times more likely to bleed, and this was irrespective of plasma administration. 20 In a more recent evaluation of the use of EACA in all cause bleeding, no correlations were found between EACA dose and dose of packed red blood cells or the packed cell volume (PCV) prior to transfusion. 21 There is perhaps even less data in the evaluation of TEA. There is only one study that retrospectively reviewed administration of TEA to dogs with various bleeding disorders. Statistically, TEA treatment did not reduce the number nor the dose of transfused blood products when compared to those not treated. 22 When given to healthy dogs, TEA administration failed to create the anti-fibrinolytic properties as expected on thromboelastographic (TEG) analysis.23 Anecdotally I would add, that clinically I use higher doses than those used in these studies. In addition, although we have some limited data suggesting therapeutic concentrations15, we lack pharmacokinetic data to validate the recommended administrative dose. All doses currently recommended have been extrapolated from human medicine, or are based on opinion. 42 Side effects of EACA and TEA in people are similar and can include gastrointestinal upset, pain/muscle aches, dizziness, headache, allergic reactions, fever, seizures, bradycardia, hypotension and thrombotic effects. Although some of these may be difficult to detect in veterinary patients, the literature thus far has failed to show dramatic adverse effects. In the retrospective evaluation of TEA on all causes of bleeding, no adverse events were seen.22 When TEA was administered to healthy dogs, vomiting was noted, but only at higher dosages.23 In 122 dogs treated with EACA for various bleeding disorders, only 3 experienced possible drug related adverse effects. These included diarrhea, decreased appetite, and toenail loss. The latter was noted with administration of the drug for 2 months.21 In summary, given the high cost of blood products, the potential risks associated with their administration, and the fact that cost of veterinary care can drive some owners to the decision of euthanasia, antifibrinolytic drugs may offer a novel, low cost solution for patients at risk of bleeding. As is always the case with veterinary medicine addition research is needed into the areas of safety, efficacy and appropriate dosing. References: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. Prittie JE. Triggers for use, optimal dosing, and problems associated with red cell transfusions. Vet Clin North Am Small Animal Pract 2003; 33: 1261-1275. Carless PA, Henry DA, et al. Transfusion thresholds and other strategies for guiding allogenic red blood cell transfusion. Cochrane Database Syst Rev 2010; 10:CD002042. Palmer, L, Martin LM. Traumatic coagulopathy-Part 1: Pathophysiology and diagnosis 2014; 24 (1): 63-74. Yoo SH, Venn E, et al. Thromboelastographic evidence of inhibition of fibrinolysis after aminocaproic acid administration in a dog with acute traumatic coagulopathy. J of Vet Emer Crit Care 2016: 26 (5): 737-742. Fletcher DJ, Rozanski EA, et al. Assessment of the relationships among coagulopathy, hyperfibrinolysis, plasma lactate, and protein C in dogs with spontaneous hemoperitoneum. J of Vet Emer Crit Care 2016; 26(1): 41-51. Kananagh C, Shaw S, et al. Coagulation in hepatobiliary disease. J of Vet Emer Crit Care 2011; 21(6); 589-604. Lara-Garci A, Couto CG, et al. Postoperative Bleeding in Retired Racing Greyhounds. J of Vet Inter Med 2008; 22: 525-533. Marin LM, Iazbik C, et al. Retrospective evaluation of the effectiveness of epsilon aminocaprioic acid for the prevention of postamputation bleeding in retired racing Greyhounds with appendicular bone tumors: 46 cases (2003-2008). J of Vet Emer Crit Care 2012; 22(3); 332-340. Marin LM, Iazbik C, et al. Epsilon Aminocaproic Acid for the Prevention of Delayed Postoperative Bleeding in Retired Racing Greyhounds Undergoing Gonadectomy. Vet Surg 2012; 41: 594-603. Kelmer E, Segev G, et al. Effects of intravenous administration of tranexamic acid on hematological, hemostatic, and thromboelastographic analytes in healthy adult dogs. J of Vet Emer Crit Care 2015: 25(4): 495-501. Henry DA, Moxey AJ, et al. Anti-fibrinolytic use for minimizing perioperative allogenic blood transfusion. Cochrane Database Syst Rev 2001; (1): CD001886. CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 377(9771): 1096-1101. Moser KM, Guisan M, Bartimmo EE, et al. In vivo and post mortem dissolution rates of pulmonary emboli and venous thrombi in the dog. Circulation 1973; 48: 170–178. Moser KM, Cantor J, Olman M, et al. Chronic pulmonary thromboembolism in dogs treated with tranexamic acid. Circulation 1991; 83: 1371– 1379. Fletcher D, Blackstock KB, et al. Evaluation of tranexamic acid and ε-aminocaproic acid concentrations required to inhibit fibrinolysis in plasma of dogs and humans. Am J Vet Res 2014; 75: 731–738. Lang IM, Marsh JJ, Konopka RG, et al. Factors contributing to increased vascular fibrinolytic activity in mongrel dogs. Circulation 1993; 87:1990–2000. Okamoto S, Nakajima T, et al. A suppressing effect of aminocaproic acid on bleeding of dogs, produced with stimulation of plasmin in circulating blood. Keio J Med 1959; 8(4): 247-266. Lara-Garcia A, Couto CG, et al. Postoperative Bleeding in Retired Racing Greyhounds. J of Vet Med 2008; 22(3): 525-533. Marin LM, Iazbik CM, et al. Epsilon Aminocaproic Acid for the Prevention of Delayed Postoperative Bleeding in Retired Racing Greyhounds Undergoing Gonadectomy. Vet Sx 2012; 41: 594-603. Marin LM, Iazbik CM, et al. Retrospective evaluation of the effectiveness of epsilon aminocaproic acid for the prevention of postamputation bleeding in retired racing Greyhounds with appendicular bone tumors: 46 cases (2003-2008). J of Vet Emer Crit Care 2012; 222(3): 332-340. Davis M, Bracker K. Retrospective Study of 122 Dogs that Were Treated with the Antifibrinolytic Drug Aminocaproic Acid: 2010-2012. J Am Anim Hosp Assoc 2016; 52: 144-148. Kelmer E, Marer K, et al. Retrospective evaluation of the safety and the efficacy of tranexamic acid for the treatment of bleeding disorders in dogs. Isr Vet Med J 2013; 68(2): 94-100. Kelmer E, Segev G, et al. Effects of intravenous administration of tranexamic acid on hematological, hemostatic and thromboelastographic analytes in healthy adult dogs. J Vet Emer Crit Care 2015; 25(4): 494-501. 43 Topsy, Turvy, Twisty, Turny: Untangling Imaging of Torsions and Volvuluses Alaina H. Carr, DVM, DACVR Seattle Veterinary Specialists Kirkland, WA Introduction Torsions and volvuluses are uncommon events in veterinary patients, but when present, usually signify a surgical emergency, with variable prognosis depending on the organ affected, chronicity of pathology, and degree of vascular compromise. A torsion can be defined as twisting of a body part or organ around its own axis, and a volvulus is defined as rotation of an organ around itself and the mesentery that supports it. However, in veterinary medicine these terms can be used interchangeably. All of the diagnoses discussed below will often present with non-specific clinical signs and have particular imaging findings that aid diagnosis. Lung Lobe Torsion Lung lobe torsion occurs when a lobe rotates longitudinally, usually at the hilus. This results in occlusion of the pulmonary veins, lymphatics and bronchi but arterial blood vessels often remain initially patent, causing congestion. It can occur in both dogs and cats but is more commonly recognized in the canine. Affected patients have a wide age range and may present with respiratory signs (coughing, dyspnea, hemoptysis) or less specific signs (lethargy, anorexia, pyrexia). There may be reduced heart/lung sounds on thoracic auscultation. Based on the literature, underlying pulmonary pathology is less commonly present but underlying or concurrent pleural pathology- especially chylous effusion- is more frequently identified. Potential predisposing factors include trauma, chronic pleural disease, diaphragmatic hernia and pulmonary parenchymal disease but multiple case reports are also characterized by spontaneous torsion with no known underlying cause. However, effusions may develop after lung torsion, if not previously present, due to lung congestion and necrosis, as well as decreased pleural lymphatic drainage. There appears to be a breed (or at least a body conformation) predisposition. Deep chested dogs such as Afghans and Whippets have a tendency to torse their right middle lung lobe, thought to be due to the long, narrow lung shape and loose attachments. However, barrel chested/small chondrodystrophic dogs such as Pugs (overrepresented breed) can also present with lung lobe torsion, but tend to torse their left cranial lung lobe, which can lack the mediastinal attachments of other lobes. Lung lobe torsions are uncommon in cats but have been reported in the right cranial/middle lung lobes. Radiographic hallmarks of lung lobe torsion include a vesiculated gas pattern (78%) which can progress in severity on serial radiographic exams, atypical positioning and enlargement of the affected lung which can cause a contralateral mediastinal shift or an ipsilateral shift due to atelectasis (likely earlier in disease progression), pleural effusion (100%) which may be distributed more to the ispilateral side as the lung lobe torsion, and bronchial narrowing, attenuation or abnormal positioning. The vesiculated gas pattern may occur secondary to a variety of underlying causes, including bronchial tearing resulting in air trapping from a one-way valve effect, necrosis or anaerobic infection. Air bronchograms may be present initially in affected lung, but often disappear over time with progressive congestion and filling of the bronchus with fluid. Pneumomediastinum or pneumothorax may occur secondary to bronchial tearing. Differentials for lung lobe torsion can include pneumonia, contusion or coagulopathy, neoplasia, atelectasis, pulmonary thromboembolism, herniation, pyothorax, inflammation secondary to a migrating foreign body, or pulmonary abscess. Computed tomography (CT) findings are overall similar to those reported radiographically, but CT allows for more definitive evaluation of bronchial position or attenuation. Lack of contrast enhancement in the affected lung has also been reported, and in some cases CT allows for detection of underlying or concurrent intra-thoracic pathology that may not be 44 visible radiographically, but may change prognosis and long-term therapeutic recommendations. Most importantly, pleural effusion does not represent a significant limitation on CT, compared to radiographic examination. Initial therapy is aimed at improving respiratory function with oxygen supplementation, removing pleural effusion and cardiovascular stabilization as needed. Antibiotic therapy may be appropriate if there is suspicion for secondary infection. Exploratory thoracotomy and lung lobectomy are the definitive treatment, and lung lobe torsion is considered a surgical emergency with improved prognoses associated with prompt recognition and treatment. Prognosis is moderate to fair for recovery but is partially dependent on any underlying pathology. Gastric Dilation-Volvulus (GDV) Gastric dilation-volvulus is a well-recognized disorder resulting from rotation of the stomach, most commonly approximately 180 degrees. Large breed dogs are over-represented; possible underlying causes and predisposing have been discussed at length. Patients frequently present for signs of abdominal discomfort, abdominal distension, retching behavior, anorexia or hypovolemic shock. However, many less-well recognized variations of GDV have been reported as well, and identification of these variants, as well as differentiation of GDV from other gastric pathology, is important both for diagnosis and prognosis. A single right lateral radiograph of the abdomen has been reported to be the only view needed for diagnosis of GDV in 90% of patients. Additional views may be needed in less straightforward cases, to more accurately characterize other organs such as the spleen and small intestine, and to aid recognition of additional lesions which may have prognostic value. Classic radiographic signs of a 180 degree gastric dilation with volvulus include severe gas dilation of the stomach, with displacement of a gas-filled pylorus to the dorsal aspect of the abdomen (as seen on a right lateral projection). Diffuse variable dilation of the small bowel is usually present due to a combination of aerophagia and functional ileus (attributed to altered blood flow through mesenteric vessels). Gas dilation of the esophagus is also frequently identified. The spleen is usually abnormally positioned as well, and varies in size but is most frequently enlarged. Differentials for GDV include severe distension of the stomach secondary to aerophagia, obstruction (pyloric or proximal small intestinal), or ‘food bloat.’ However in these cases, the pylorus should still be normally positioned, and abnormal splenic position/small intestinal ileus are usually not present. A left lateral projection of the abdomen is usually most helpful for assessment of the pylorus when it is in a normal position. Variations in the classic appearance of a GDV can include pneumatosis, other degrees of rotation such as 360 degrees, or gastric torsion. Gastric pneumatosis is visualized as a thin, irregular linear, curvilinear or cystic region of gas within/parallel to the gastric wall, identified within the fundus or body. Pneumatosis may present in conjunction with pneumoperitoneum, which can be iatrogenic if trocharization has occurred prior to radiographic exam. Pneumatosis has not been shown to accurately predict gastric wall necrosis at surgery; if present there is a 40% chance that the patient will require gastric resection but lack of pneumatosis does not decrease the possibility of the presence of necrosis. Radiographic signs of 360 degree torsion include severe gas distension of the stomach which may be relatively more severe than identified with 180 degree torsions, and more variable visualization/definition of the pylorus. Dorsal or medial displacement of the descending duodenum can be appreciated, and a “J” or “hook” shaped segment of gas filled bowel may be seen cranial to the stomach, represented a gas filled duodenum wrapped around the cardia. Severe splenic displacement is also appreciated. Gastric torsion occurs when the stomach twists on its long axis, causing compartmentalization of the stomach into orad/fundic and aborad/pyloric segments. Variable displacement of the small bowel into the cranial/dorsal abdomen may occur, and the spleen is displaced as well. Small intestinal ileus is usually present. 45 Use of additional imaging modalities are usually unnecessary for diagnosis and may delay treatment (exploratory laparotomy for de-rotation, possibly partial gastrectomy and/or splenectomy if indicated). Colonic Torsion/Volvulus Intestinal or colonic torsion occurs when the bowel twists on its long axis, potentially resulting in a mechanical obstruction, as opposed to a volvulus which occurs when there is rotation about the mesentery (mesenteric torsion is discussed below). Colonic torsion/volvulus usually affects young to middle aged, medium and large breed dogs. Patients present with non-specific GI signs, most commonly diarrhea although vomiting, mild abdominal distension, abdominal pain, lack of feces and tenesmus have often been described. Clinical signs may be partially dependent on whether the colon has undergone a torsion or a volvulus. Patients may also present in hypovolemic shock. There may be a predisposition in patients with previous gastric dilation/volvulus or other disorders of gastrointestinal motility. Inclusion of the cecum in the volvulus (ceco-colic volvulus) has been reported to involve the cranial mesenteric artery; when this occurs there is impairment of blood flow to the small bowel as well, similar to the etiology of a full mesenteric volvulus. Radiographic signs of colonic torsion include severe fluid or gas dilation of the colon, altered colonic location, and altered location/inability to visualize the ileocolic junction and cecum. Concurrent small intestinal ileus may be identified. Splenic position is normal. Ultrasonographically, a fluid or gas-distended colon in an abnormal position is again identified. Sites of luminal narrowing may or may not be visualized; the cecum and ileocolic junction may be difficult to identify, or in an abnormal position. Additionally, mesenteric vessels can sometimes be visualized in an abnormal position, with altered or diminished blood flow on Doppler interrogation. Treatment involves exploratory laparotomy, with de-rotation of the colon. Partial colonic resection may be needed if necrosis is identified. Prognosis varies depending on severity of colonic wall viability. Mesenteric Volvulus Mesenteric volvulus occurs when the intestine twists around the root of the mesentery, causing ischemia and eventual necrosis due to occlusion of the cranial mesenteric artery. Mesenteric volvulus is differentiated from intestinal torsion, which occurs when the bowel twists longitudinally or around a loop of itself. Patients present with acute, rapid onset of severe cardiovascular compromise and abdominal distension; other signs such as vomiting, retching and hematochezia have also been reported. This is most commonly reported in male, adult, medium and large-breed dogs (German Shepherd dogs and English Pointers are more frequently reported). Volvulus may involve part of the small bowel, the entire small bowel, and/or the cecum/proximal colon. Concurrent gastric-dilation volvulus has been also reported. Mortality rates are high, reported to range from 42% to 100%. Risk factors have not been definitively identified, but conditions that have been hypothesized to increase risk of torsion include exocrine pancreatic insufficiency, prior surgery (with or without adhesion formation), intestinal parasitism or viral infections, foreign body obstruction, IBD, trauma, pregnancy/parturition, and GDV. Radiographic signs of mesenteric volvulus include severe, diffuse gas and fluid dilation of the small intestine, usually with no indications of peristalsis. Serosal detail may be decreased due to peritonitis or fluid accumulation. Similarly, ultrasound will also identify severe diffuse intestinal dilation with lack of motility. Intestinal wall layering may be decreased with transmural thickening and loss of wall layer distinction. Doppler interrogation will identify severe decreased or absent blood flow within the intestinal wall and mesenteric 46 vessels, and the position of the mesenteric vessels may be abnormal. Computed tomography has been shown to be helpful in diagnosis of mesenteric volvulus as well; contrast-enhanced CT can detect a spiral shape and narrowing of the arteries (“whirl sign”), venous congestion, as well as diffuse intestinal pathology. Surgical intervention for de-rotation is required for treatment; prompt recognition and surgery may improve outcome. Survival rates may be higher when rotation is less than 180 degrees and with rapid diagnosis/surgery. Even if an adequate portion of the bowel remains viable (a significant portion of patients are euthanized at surgery due to widespread intestinal necrosis), patients may succumb to reperfusion injury, and short bowel syndrome can occur if massive intestinal resection is required. Splenic Torsion Torsion of the spleen occurs when the spleen rotates around, or there is disruption of the gastrosplenic and/or splenocolic ligaments. It is an uncommon diagnosis when not associated with GDV, but constitutes a surgical emergency. Splenic torsion most commonly occurs in large to giant breed dogs, usually with deep-chested conformation such as German Shepherds and Great Danes. Males seem to be more commonly affected than females. Definitive underlying etiology is unclear but GDV has been identified as a predisposing factor or comorbidity. Patient presentation is non-specific with signs of acute abdomen such as anorexia, lethargy, vomiting, depression, retching and abdominal distension/discomfort, but patients have also been reported to present with more chronic signs in cases of chronic, intermittent or partial torsion. Patients may also present with signs of hypovolemic shock. A mass may be palpable, representing distension and abnormal positioning of the spleen. Patients may have anemia or leukocytosis but overall bloodwork is usually non-specific. Abdominal fluid may be a pure transudate, exudate or hemorrhagic. Radiographic findings of splenic torsion include decreased serosal detail, enlargement and abnormal position of the spleen (“reverse C”), lack of visualization of the splenic head in the left cranial abdominal quadrant and cranial/dorsal/caudal displacement of intestine, but are often considered non-specific for splenic torsion when trying to differentiate from other splenic pathology. Appearance of the spleen may be partially dependent on chronicity of disease as well, and evaluation of the spleen can be challenging if concurrent peritoneal effusion is present. Medial displacement of the descending duodenum and ascending colon is inconsistently identified. On ultrasound, the spleen appears severely, diffusely enlarged with significant decrease in parenchymal echogenicity. The parenchyma may be heterogenous as well, with linear regions of increased echogenicity separating more hypoechoic areas. Positioning of the spleen and hilar vessels is abnormal and splenic veins may be distended, with increased echogencity of the fat at the hilus as well (a hyperechoic “triangle” may be identified between splenic veins). Vascular thrombosis can be identified and the spleen will have minimal to no Doppler signal on vascular interrogation. Differentials include a splenic mass, splenic thrombosis which can occur due to many underlying disease processes that results in a hypercoagulable state, and diffuse enlargement of the spleen can occur without torsion due to neoplastic infiltration (particularly round cell neoplasia), severe extramedullary hematopoiesis, systemic inflammation, vascular congestion as a sequelae of portal hypertension, or as an anatomic variant in certain breeds such as German Shepherds or Greyhounds. Diffuse splenic enlargement can also occur secondary to many sedatives or anesthestics, including opioids. Splenic torsion is also considered a surgical emergency. Splenectomy is the definitive treatment; on histopathology there is evidence of severe vascular congestion, potentially with necrosis depending on duration of torsion prior to intervention. Secondary bacterial infection is rare but can occur with abscess formation due to agents such as E. coli and Clostridium. The prognosis is generally good with prompt intervention. 47 References ● Thrall DE: Textbook of Veterinary Diagnostic Radiology, Saunders 6 th ed. 2013. ● Penninck D and D’Anjou MA: Atlas of Small Animal Ultrasonography, Blackwell Pub. 1st ed. 2008. ● Fossum TW: Small Animal Surgery, Mosby Co. 4th ed. 2013 ● Neath PJ, Brockman DJ, King LG. Lung lobe torsion in dogs: 22 cases (1981–1999). J Am Vet Med Assoc 2000;217:1041– 1044. ● D’Anjou MA, Tidwell AS, Hecht S. Radiographic diagnosis of lung lobe torsion. Vet Rad US 2005; 46(6):478-484. ● Seiler G et al. Computed tomographic features of lung lobe torsion. Vet Rad US 2008; 49(6): 504-508. ● Millard RP, Myers JR, Novo RE. Spontaneous lung lobe torsion in a cat. J Vet Intern Med 2008;22:671–673. ● Hansen NL et al. Segmental lung lobe torsion in a 7-week-old Pug. JVECC 2006; 16(3): 215-218. ● White RN and Corzo-Menendez N. Concurrent torsion of right cranial and middle lung lobes in a whippet. J Sm An Practice 2000; 41:562-565. ● Fischetti AJ, Saunders HM, Dobratz KJ. Pneumatosis in canine gastric dilatation-volvulus syndrome. Vet Rad US 2004; 45(3): 205-209. ● Halfacree ZJ et al. Torsion and volvulus of the transverse and descending colon in a German shepherd dog. J Small Anim Pract 2006; 47: 468-470. ● Gagnon D and Brisson B. Predisposing factors for colonic torsion/volvulus in dogs: a retrospective study of six cases (19922010). JAAHA 2013; 49(3): 169-174. ● Chow KE et al. Imaging diagnosis- Use of multiphase contrast-enhanced computed tomography for diagnosis of mesenteric volvulus in a dog. Vet Rad US 2013; 55(1): 74-78. ● Junius G et al. Mesenteric volvulus in the dog: a retrospective study of 12 cases. J Small Anim Pract 2004; 45(2): 104-7. ● Pope ER. A better prognosis for mesenteric volvulus. Clinician’s Brief July 2004. ● Spevakow AB et al. Chronic mesenteric volvulus in a dog. Can Vet J 2009; 50: 85-89. ● Patsikas MN et al. Computed Tomography diagnosis of isolated splenic torsion in a dog. Vet Rad US 2001; 42(3): 235-237. ● Konde LJ et al. Sonographic and radiographic changes associated with splenic torsion in the dog. Vet Rad US 1989; 30(1): 4145. ● Saunders HM, Neath PJ, Brockman DJ. B-mode and Doppler ultrasound imaging of the spleen with canine splenic torsion: a retrospective evaluation. Vet Rad US 1998; 39(4): 349-353. ● Mai W. The hilar perivenous hyperechoic triangle as a sign of acute splenic torsion in dogs. Vet Rad US 2006; 47(5): 487491. 48 Feline Lymphoma: Review & Treatment Update Kevin Choy BVSc (Hons), MS, DACVIM (Oncology) Seattle Veterinary Specialists Kirkland, WA Excerpt from: The Cat: Clinical Medicine & Management – 2nd Ed Chapter 31 (Lymphoma) Incidence, Etiology, and Risk Factors Lymphoma (also termed malignant lymphoma and lymphosarcoma) is the most common feline neoplasm, comprising more than half of all hemolymphatic tumors in the cat. Lymphoma can be found in cats of any age, breed, or sex, although purebred cats such as the Manx, Burmese, and Siamese appear to be overrepresented. The precise etiology of feline lymphoma in many cases is unknown; however, viral causes of feline lymphoma are well described, with both feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) infections implicated. Before the widespread use of FeLV testing and control regimens that began in the 1970s, up to 70% of diagnosed feline lymphoma was caused by FeLV infection, with a progressive decline in FeLV associated tumors over the past decades. More recent studies indicate that only 14% to 25% of cats with lymphoma have documented FeLV infection despite an overall increase in lymphoma diagnoses. Although FeLV has a direct role in tumorigenesis, FIV is thought to indirectly contribute to an increased risk of feline lymphoma by immune dysregulation resulting in amplification of oncogenic mutations and decreased immune surveillance. This association with immune dysregulation is further supported by studies evaluating over two-hundred feline renal transplant patients receiving long-term immunosuppressive therapy with cyclosporine of which 9.5-13% of cats developed lymphoma within 2 years of transplantation. FeLV infection in one study increased the risk of lymphoma 62-fold, FIV infection 6-fold, and concurrent FeLV and FIV infection 77-fold. Exposure to second-hand tobacco smoke is also reported to increase relative risk of developing lymphoma depending on duration of exposure from 2.4-fold (any exposure) to 3.2-fold (>5 years exposure). Chronic inflammation may play a role in the development of feline lymphoma. An association has been suggested between inflammatory bowel disease (IBD) and intestinal lymphoma in which one progresses to the other (IBD to small cell lymphoma to large cell lymphoma), although definitive supporting evidence is currently not well characterized. Clinical Features Cats with lymphoma exhibit a bimodal temporal pattern of clinical presentation. The first group is comprised of young cats less than 4 years old with FeLV-associated disease, typically with mediastinal lymph node involvement and pleural effusion resulting in dyspnea. The second group is comprised of mature cats 6 to 12 years of age that are serologically FeLV negative and present with alimentary (particularly intestinal) lymphoma or lymphoma in a peripheral nodal or extranodal pattern. Clinical signs of alimentary lymphoma commonly include vomiting, diarrhea, anorexia, and weight loss. An abdominal mass or diffuse thickening of the intestinal tract is often palpable in the abdomen. Non-alimentary locations for lymphoma are quite varied and can include virtually every tissue in the body; renal, mediastinal, respiratory (nasal, tracheal), CNS (brain and spinal), peripheral nodal/multicentric (lymph node), cutaneous, skeletal muscle, ocular/conjunctival, hepatobiliary, cardiac, pericardial and uterine lymphoma have been reported in the cat, with clinical signs referable to the respective organ system dysfunction. Paraneoplastic syndromes such as hypercalcemia can also be seen, but are less common than in canine lymphoma. Prevalence, presenting clinical signs, and biological behavior of feline lymphoma vary significantly with geographical location and may reflect regional differences in feline populations as well as differences in retroviral strains and prevalence. 49 Diagnosis and Staging Because feline lymphoma is a neoplasm of the lymphoid system that has the ability to affect multiple locations, a thorough diagnostic evaluation is recommended to confirm diagnosis and anatomic localization(s) and to establish baseline data to guide prognostication and therapy. Clinically, it is most useful to classify feline lymphoma by anatomic location rather than the traditional World Health Organization (WHO) staging scheme commonly used in dogs, with each site of origin each having different presentation, clinical behavior, therapy considerations, and prognosis (Table 1). Diagnosis of most anatomic forms of lymphoma in the cat can be made from cytologic examination of fineneedle aspirates of an enlarged lymph node, affected tissues, or cavitary fluids (e.g., pleural effusions in mediastinal lymphoma). When cytologic findings are equivocal, histopathology with immunohistochemistry (for B- and T-cell phenotyping) are recommended. Histopathology is particularly important in diagnosis of alimentary lymphoma in which endoscopic (partial thickness) or surgical (full thickness) biopsies of the gastrointestinal tract are generally required for a diagnosis to differentiate between severe lymphoplasmacytic enteritis/inflammatory bowel disease (IBD) and malignant lymphoma as they both can have similar ultrasonographic appearance with diffuse thickening of the muscularis propria (with no loss of intestinal wall layering). As such, inclusion of the intestinal muscularis is necessary for a definitive diagnosis of lymphoma. Full thickness surgical biopsy is considered a superior diagnostic method though is more invasive. If histopathology is inconclusive, molecular analysis techniques such as flow cytometry and polymerase chain reaction for antigen receptor rearrangement (PARR) test for T and B cell receptor gene clonality assessment can provide further support for malignancy, but sensitivity and specificity of this test is highly dependent on methodology and primers specific to each testing laboratory. Other described biomarkers for differentiating between IBD and alimentary lymphoma include Bcl-2 gene expression, serum LDH and serum thymidine kinase activity though few are routinely used and commercially available to diagnostic laboratories for clinical use. Nasal lymphoma also commonly requires a biopsy using a blind or rhinoscopic approach, with immunohistochemistry useful in definitively confirming a nasal lymphoma diagnosis. Advanced imaging such as computed tomography (CT) is helpful in further differentiating inflammatory vs neoplastic disease and extent of tumor burden. After the diagnosis of lymphoma, complete staging should include a detailed physical examination, with particular attention to lymph node size (including tonsils), abdominal palpation (masses, thickened intestinal loops, organomegaly), cranial thoracic compression (to screen for mediastinal mass), and ophthalmic examination. Peripheral lymphadenopathy (seen in nodal lymphoma) is less frequently observed in cats than in dogs. Laboratory evaluation should include a CBC, serum biochemistry profile, urinalysis with culture and sensitivity (to assess for preexisting urinary tract infections that may represent a nidus for sepsis during myelosuppressive chemotherapy), and FIV and FeLV serology. Three-view thoracic radiographs (right lateral, left lateral, and ventrodorsal views) should be made to assess lymph node, pulmonary, mediastinal, and pleural structures. Abdominal ultrasound examination is useful to assess gastrointestinal wall thickness, mesenteric lymph node size, and organ size and echotexture (liver, spleen, and kidney). Ultrasound-guided fine-needle aspirates should be performed where appropriate. Bone marrow aspirates should also be considered as part of complete staging, particularly in patients with unexplained cytopenias or if cytologic diagnosis of lymphoma has not been confirmed despite prior staging diagnostics and high clinical suspicion. If abnormal or elevated circulating lymphocytes are noted, flow cytometry of peripheral blood may also helpful in characterizing this cell population. Complete staging with anatomic classification will guide appropriate therapy selection, minimize toxicity, and reduce therapy-associated complications. 50 TABLE 1: Summary of Selected Anatomic Forms of Lymphoma in Cats Anatomic Form Prevalence Median Age (y) Common Phenotype General Prognosis Treatment Modality Comments Gastrointestinal -small cell (low grade) Common 13 T-cell Fair to good Chemotherapy Typically responds well to less aggressive oral maintenance protocols Moderate 10 B-cell Poor Chemotherapy +/- Surgery Uncommon <4 T-cell Poor to fair Chemotherapy Nodal Nodal Uncommon 7 - Poor Chemotherapy Extranodal - Nasal Uncommon 9.5 B-cell Good - Laryngeal/tracheal Rare 9 - Fair to good - Renal Rare 9 B-cell Poor Radiation Chemotherapy Chemotherapy +/- Radiation Chemotherapy - Hepatic (primary) - Cutaneous Rare Rare 12 10-13 T-cell T-cell Poor Fair - Occular Rare 10 B-cell Fair - CNS Rare 4-10 - Poor -large cell (intermediate/high grade) Mediastinal Mediastinal Chemotherapy Chemotherapy +/- Surgery Surgery +/Chemotherapy Chemotherapy +/- Radiation FeLV-negative patients may have longterm remissions Elevated risk of CNS metastasis Elevated risk of CNS metastasis Biological Behavior Most anatomical classifications of feline lymphoma start as localized (non-Hodgkin–like) disease that tends to progress to systemic involvement over time as opposed to multicentric disease seen commonly in dogs and humans. Because of the anatomic syndromic nature of lymphoma in cats, the clinical signs associated with the site of origin are most important for prognostication. Lymphoma immunophenotype varies by location, etiology and anatomic form ((can help in the diagnosis of anatomic forms of lymphoma (Table 1). Age, weight, sex, FIV status and stage (based on WHO criteria)) also do not appear to be prognostic in cats. FeLV infection has been shown by some studies to be a negative prognostic factor because of a more rapid emergence of drug resistance, but other studies have not found a similar association. The most important prognostic factor for feline lymphoma are anatomic localization of disease and response to therapy, particularly within the first few weeks of treatment. Treatment and Prognosis Systemic chemotherapy is the primary treatment modality for most anatomic forms of feline lymphoma, with surgery or radiotherapy being options in specific forms that are solitary or localized. Without medical therapy mortality rates in cats with lymphoma are approximately 40% and 75% at 4 and 8 weeks after diagnosis, respectively. A substantial amount of literature exists on the many anatomic forms of feline lymphoma, each 51 with a highly variable treatment regimens and prognoses that is outside the scope of this chapter to describe each form in detail. A selection of the most commonly encountered clinical presentations are described in the following sections. Alimentary (gastrointestinal) lymphoma is the most commonly diagnosed anatomic form in cats. The two most common forms of alimentary lymphoma are (1) low-grade small T-cell lymphomas principally confined to the mucosa but diffusely distributed in the small intestine, and (2) intermediate to high-grade large B-cell or T-cell lymphomas that are transmural, causing destruction of normal intestinal wall layering and can affect focal or multi-focal regions of the gastrointestinal tract. Low-grade gastrointestinal lymphoma (also termed lymphocytic intestinal lymphoma) is considered a slowgrowing, indolent neoplasm that can be managed successfully with maintenance oral chemotherapy. Combination of daily prednisone or prednisolone (2 mg/kg orally daily tapering to 1 mg/kg orally every 48 hours over several weeks) and chlorambucil therapy (20 mg/m orally every 2 weeks, favored by the author) or 15 mg/m orally every 24 hours for 4 consecutive days every 3 weeks has been reported. Prognosis is typically good, with overall response rates of up to 96%, up to 76% of cats achieving complete remission, and median clinical remission durations of approximately 19 to 30 months or longer reported. In the event of clinical relapse, many cats with small cell lymphoma can be successfully with alternate oral alkylator chemotherapy regimens including cyclophosphamide and lomustine. Please refer to Chapter 23 for further information on the management of gastrointestinal small cell lymphoma. Intermediate to high-grade gastrointestinal lymphomas are aggressive with rapid disease progression and shorter duration of remission and survival. As such multi-agent chemotherapy is considered the standard of care, with a variety of protocols and response rates reported. However, there is a general lack of consensus regarding the gold-standard protocol. Consequently, many treatment regimens are specific to a particular institution or practice. Multiple variations of the multi-agent protocol COP (cyclophosphamide, vincristine, and prednisone) have been reported to result in complete remission in 50% to 75% of cats, with a median survival time (MST) ranging from 2 to 10 months. Single-agent doxorubicin chemotherapy has been less successful than in dogs, with a response rate of 42% and median duration of response of 64 days in cats. However, when doxorubicin is included into multi-agent protocols either as part of a CHOP (H = doxorubicin) protocol or as maintenance therapy (COP followed by doxorubicin), significantly longer durations of remission have been reported in cats that responded compared with cats that received only COP therapy. These reports suggest that a subset of cats may benefit from the addition of doxorubicin. Doxorubicin has been reported to be nephrotoxic and cardiotoxic in cats; thus a COP-based protocol may be preferable for cats with preexisting renal or cardiac disease, but consultation with a veterinary oncologist is recommended before starting induction therapy. The most reliable prognostic indicator is response to therapy; individuals achieving complete remission typically enjoy the best outcomes, with MST approaching 1 year and longer-term survival reported. Conversely, failure to achieve complete remission is generally associated with MST of several weeks. Singleagent therapy with prednisolone at 2 mg/kg orally once daily for 2 weeks and then tapered to 1 mg/kg thereafter may provide varying degrees of palliation, with reported MST of approximately 30-60 days. Alternate and rescue protocols are not well defined in cats. Single-agent lomustine (CCNU) has been used in cats as primary therapy or in a rescue setting at reported dosages of 30 to 60 mg/m orally every 3 to 6 weeks depending on degree and duration of myelosuppression. The advantages are simplicity, and relative lower cost, but response rates, long term survival and toxicity are less well defined. A recent retrospective study evaluating 32 cats receiving maintenance oral lomustine chemotherapy as first line therapy revealed a response rate of 50% with median duration of response of 302 days (64-1450) and overall MST of 108 days (4-1488). Chronic 52 administration of lomustine has been associated with severe thrombocytopenia and pulmonary fibrosis in cats and regular thoracic radiographs should be considered in patients receiving long term lomustine chemotherapy. Regular biochemical monitoring for hepatotoxicity should also be performed in cats receiving lomustine, though apparent risk may be low, with only 2 of 29 cats (6.8%) developing elevations ALT in in one report following at least one dose of lomustine. Whole-abdomen irradiation has been used as adjuvant or rescue therapy for gastrointestinal lymphoma. In one pilot study eight cats with gastrointestinal or abdominal lymphoma that achieved remission during an abbreviated 6-week CHOP chemotherapy protocol received abdominal radiation therapy 2 weeks later. Five cats remained in remission for at least 266 days after starting therapy, with a range from 266 to 1332 days. In another study a rapid abdominal radiation protocol delivered over 2 days for cats with relapsed or chemotherapy-resistant gastrointestinal lymphoma resulted in a response in 10 of 11 cats, with a postirradiation MST of 214 days. Mediastinal lymphoma can involve the thymus, mediastinal and sternal lymph nodes. Pleural effusion with resulting dyspnea is a common presentation. Hypercalcemia is not a common feature. Affected cats tend to be young (2-4 years) and FeLV positive with a T-cell phenotype. FeLV infection has been shown by some studies to be a negative prognostic factor because of a more rapid emergence of drug resistance, but other studies have not found a similar association. Mediastinal lymphoma FeLV-positive cats typically have a poor prognosis with MST of less than 2-3 months due to poor response to COP or CHOP-based protocols. A recent study of mediastinal lymphoma in FeLV-negative cats however revealed significantly higher remission rates approaching 95% with no significance difference between COP or CHOP based protocols. Overall median survival of these cats on COP based chemotherapy was 484 days (20-980d) with cats that achieved complete remission surviving much longer (980 days vs 42 days respectively). Nodal lymphoma is the form of lymphoma describing disease limited to peripheral lymph nodes. While common in dogs and humans, this presentation is uncommon in cats. Peripheral nodal lymphoma has been reported to be the most common anatomic form of the disease in cats under 1 year. A distinct form of nodal lymphoma is “Hodgkin’s-like” lymphoma that typically present with enlarged mandibular or cervical lymph nodes only. Pathology of affected lymph nodes typically have classic Reed-Sternberg-like cells and is frequently described as a “T-cell rich, B-cell lymphoma”. Prognosis and treatment is highly variable and dependent on clinical presentation and extent of lymph node involvement. Localized lymph node involvement with no systemic disease may respond to radiation therapy or surgical removal of the affect nodes with reported survival of a year. However, recurrence is common. Generalized nodal lymphoma may respond to systemic chemotherapy but will depend on type of lymphoma with the author using chlorambucil- and prednisolonebased therapies for low-grade forms and COP or CHOP-based protocols for high-grade forms. Nasal lymphoma is the most common extranodal lymphoma in cats. It is typically localized with fewer than 20% of cats presenting with distant metastasis. Primarily seen in older cats (9-10 years old), the majority are intermediate to large B-cell epitheliotropic lymphomas. Because lymphocytes are highly radiosensitive, so definitive multi-fraction radiation therapy protocols (consisting of 15-20 doses of radiation) are effective for treating localized lymphoma with complete remission rates of 75-95% reported and MST ranging from 1.5-3 years. Hypo fractionated radiation protocols consisting of 2-6 doses of radiation reported in a recent study also showed benefit, with improvement in clinical signs in 86% of cats, but more modest improvement in overall survival of 432 days. Nasal lymphoma is also moderately responsive to systemic chemotherapy (COP or CHOP based) with reported response rates of 75% and survival times ranging from 1-2 years in cats that achieve complete remission. 53 Renal Lymphoma is the second most common extranodal lymphoma in cats, arising in one or both kidneys. Most are intermediate to high-grade B-cell phenotype. Cats with renal lymphoma have a 40-50% risk of CNS metastasis. As such, it is recommended to include a form of chemotherapy that crosses the blood brain barrier, such as cytosine arabinoside, to a standard COP protocol (COAP) to reduce risk of CNS metastasis. Large granular lymphoma is an uncommon, morphologically distinct variant of lymphoma in cats that carries a poor prognosis. This population of cells represent cytotoxic T-cells and NK cells with characteristic cytoplasmic azurophilic granules on pathology. Response to chemotherapy is generally poor with a reported MST from 4557 days in cats that responded to COP based chemotherapy. Regardless of the anatomic form, most cats with lymphoma benefit from supportive care, particularly cats that are anorexic, vomiting, or severely debilitated because of chronic disease progression. Nutritional and fluid support is critical for cats that are inappetent because of either the malignancy or the chemotherapy. This is particularly important in alimentary lymphoma where body weight changes during chemotherapy has been seen to be a significant prognostic indicator with cats. Cats with stable to increased body weight during the first 4 weeks of treatment surviving much longer than patients that lost >5% of their starting weight with MST 7m (463) versus 3.1m (2.3-5.1) respectively. The placement of an esophageal, gastric, or jejunal feeding tube (bypassing the affected tissues) can allow adequate nutrition, hydration, and administration of oral medication, particularly during early stages of treatment. Appetite stimulants, anti-emetics, and thorough nursing care may also be necessary to improve body condition and tolerance to therapy. Selected References 1. Little S. The Cat: Clinical Medicine & Management. 1st edition. St Louis, Saunders; 2011. Chapter 31, Feline Lymphoma p. 782-786 (Choy K, Bryan J) 2. Little S. The Cat: Clinical Medicine & Management. 2nd edition. St Louis, Saunders; 2017. Chapter 31, Feline Lymphoma (Choy K, Bryan J) 3. Meuten DJ: Tumors in domestic animals, ed 4, Ames, Iowa, 2002, Blackwell, pp 144-151. 4. Withrow SJ, Vail DM: Withrow and MacEwen’s small animal clinical oncology: feline lymphoma and leukemia, St Louis, 2013, Saunders, pp 638-653. 5. Argyle DJ, Brearly MJ, Turek MM: Decision making in small animal oncology—feline lymphoma and leukemia, Ames, Iowa, 2008, Wiley-Blackwell, pp 197-209. 6. Bryan JN: Feline lymphoma. In Henry CJ, Higginbotham ML, editors: Cancer management in small animal practice, ed 1, St Louis, 2010, Saunders Elsevier, pp 348-351. 7. Beatty J: Viral causes of feline lymphoma: retroviruses and beyond, Vet J Aug;201(2):174-80, 2014. 8. Wormser C, Mariano A, Holmes ES, et al: Post-transplant malignant neoplasia associated with cyclosporine-based immunotherapy: prevalence, risk factors and survival in feline renal transplant recipients, Vet Comp Oncol Oct 10, 2014. 9. Durham AC, Mariano AD, Holmes ES, et al: Characterization of post transplantation lymphoma in feline renal transplant recipients, J Comp Pathol, Feb-Apr;150(2-3):162-8, 2014 10. Richter KP: Feline gastrointestinal lymphoma. In Bonagura JR, Twedt DC, editors: Kirk’s current veterinary therapy XIV, St Louis, 2009, Saunders, pp 340-342. 11. Moore A: Extranodal lymphoma in the cat: Prognostic factors and treatment options, J Feline Med and Surgery 15, 379-390; 2013. 12. Fabrizo F, Calam AE, Dobson JM, et al: Feline mediastinal lymphoma: a retrospective study of signalment, retroviral status, reponse to chemotherapy and prognostic indicators, J Feline Med Surg Aug;16(8):637-44, 2014. 13. Kleinschmidt S, Harder J, Nolte I, et al: Chronic inflammatory and non-inflammatory diseases of the gastrointestinal tract in cats: diagnostic advantages of full-thickness intestinal and extra intestinal biopsies, J Feline Med Surg Feb;12(2):97-103, 2010. 14. Scott KD, Zoran DL, Mansell J, et at: Utility of endoscopic biopsies of the duodenum and ileum for diagnosis of inflammatory bowel disease and small cell lymphoma in cats, J Vet Intern Med, Nov-Dec;25(6):1253-7, 2011. 15. Barrs VR, Beatty JA: Feline alimentary lymphoma: 1. Classification, risk factors, clinical signs and non-invasive diagnostistics, J Feline Med Surg, Mar;14(3):182-90, 2012 16. Russell KJ, Beatty JA, Dhand N, et al: Feline low-grade alimentary lymphoma: how common is it?, J Feline Med Surg, 54 Dec;14(12):910-2, 2012. 17. Al-Ghazlat S, de Rezende CE, Ferreri J: Feline small cell lymphosarcoma vs inflammatory bowel disease; diagnostic challenges, Compend Contin Educ Vet, Jun;25(6):E1-5; quiz E6, 2013. 18. Burkhard MJ, Bienzle D: Making sense of lymphoma diagnostics in small animal patients, Clin Lab Med Sep;35(3):591-607, 2015. 19. Amores-Fuster I, Cripps P, Graham P, et al: The diagnostic utility of lymph node cytology samples in dogs and cats, J Small Animal Pract, Feb;56(2):125-9, 2015. 20. Ku CK, Kass PH, Christopher MM: Cytologic-histologic concordance in the diagnosis of neoplasia in canine and fline lymph nodes: a retrospective study of 367 cases, Vet Comp Oncol Aug 15, 2016. 21. Schleis SE: Cancer screening tests for small animals, Vet Clin North Am Small Anim Pract, Sepl44(5):871-81, 2014. 22. Burkhard MJ, Bienzle D, Making sense of lymphoma diagnostics in small animal patients, Vet Clin North Am Small Anim Pract, Nov;43(6):1331-47, 2013. 23. Guzera M, Cian F, Leo C, et al: The use of flow cytomtetery for immunophenotyping lymphoproliferative disorders in cats: a retrospective study of 19 cases, Vet Comp Oncol Aug;14 Suppl 1:40-51, 2016. 24. Patterson-Kane JC, Kugler BP, Francis K: The possible prognostic significance of immunophenotype in feline alimentary lymphoma: a pilot study, J Comp Pathol 130:220, 2004. 25. Milner RJ, Peyton J, Cooke K et al: Response rates and survival times for cats with lymphoma treated with the University of Wisconsin-Madison chemotherapy protocol: 38 cases (1996-2003), J Am Vet Med Assoc 227:1118, 2005. 26. Moore AS, Cotter SM, Frimberger AE et al: A comparison of doxorubicin and COP for maintenance of remission in cats with lymphoma, J Vet Intern Med 10:372, 1996. 27. Ettinger SN: Principles of treatment for feline lymphoma, Clin Tech Small Anim Pract 18:98, 2003. 28. Jarrett WF, Crighton GW, Dalton RG: Leukaemia and lymphosarcoma in animals and man. I: Lymphosarcoma or leukaemia in domestic animals, Vet Rec 79:693, 1966. 29. Zwahlen CH, Lucroy MD, Kraegel SA et al: Results of chemotherapy for cats with alimentary malignant lymphoma: 21 cases (1993-1997), J Am Vet Med Assoc 213:1144, 1998. 30. Krick EL, Moore RH, Cohen RB, Sorenmo KU: Prognostic significance of weight changes during treatment of feline lymphoma, J Feline Med Surg, Dec;13(12):976-83, 2011. 31. Barrs VR, Beatty JA: Feline alimentary lymphoma: 2. Further diagnostics, therapy and prognosis, J Feline Med Surg, Mar;14(3):191-201, 2012. 32. Gustafson TL, Villamil A, Taylor BE, et al: A retrospective study of feline gastric lymphoma in 16-chemotherapy treated cats. J Am Anim Hosp Assoc, Jan-Feb;50(1):46-52, 2014. 33. Krick EL, Cohen RB, Gregor TP, et al: Prospective clinical trial to compare vincristine and vinblastine in a COP-based protocol for lymphoma in cats, J Vet Intern Med, Jan-Feb;27(1):134-40, 2013. 34. Kristal O, Lana SE, Ogilvie GK, et al: Single agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19 cases (1994-1997), J Vet Intern Med 15:125, 2001. 35. Rau SE, Burgess KE. A retrospective evaluation of lomustine (CeeNU) in 32 treatment naïve cats with intermediate to large cell gastrointestinal lymphoma (2006-2013), Vet Comp Oncol Jun 9, 2016. 36. Dutelle AL, Bulman-Feliming JC, Lewis CA, et al: Evaluation of lomustine as a rescue agent for cats with resistant lymphoma, J Feline Med Surg, Oct;14(10):694-700, 2012. 37. Skorupski KA, Durman AC, Duda L et al: Pulmonary fibrosis after high cumulative dose nitrosourea chemotherapy in a cat, Vet Comp Oncol 6(2):120, 2008. 38. Williams LE, Pruitt AF, Thrall DE: Chemotherapy followed by abdominal cavity irradiation for feline lymphoblastic lymphoma, Vet Radiol Ultrasound 51:681, 2010. 39. Parshley DL, LaRue SM, Kitchell B et al: Abdominal irradiation as rescue therapy for feline gastrointestinal lymphoma: a retrospective study of 11 cats (2001-2008), J Fel Med Surg 13:63, 2011. 40. Taylor SS, Goodfellow MR, Browne WJ et al: Feline extranodal lymphoma: response to chemotherapy and survival in 110 cats, J Small Anim Pract 50:584, 2009. 41. Fujiwara-Igarashi A, Fujimori T, Oka M, et al: Evaluation of outcomes and radiation complications in 65 cats with nasal tumors treated with palliative hypofractionated radiotherapy. Vet J Dec;202(3):455-61, 2014. 42. Sfiligoi G, Theon AP, Kent MS: Response of nineteen cats with nasal lymphoma to radiation therapy and chemotherapy, Vet Radiol Ultrasound 48(4):388, 2007. 43. Mooney SC, Hayes AA, Matus RE et al: Renal lymphoma in cats: 28 cases (1977-1984), J Am Vet Med Assoc 191:1473, 1987. 55 Indolent and Less Common Canine Lymphoma Nicholas Szigetvari, MS, DVM (Board eligible) Seattle Veterinary Specialists Downtown Seattle Classifying lymphoma Lymphoma is a cancer comprised of over fifteen different subtypes that are classified based on immunophenotype (T-cell vs B-cell), anatomic location, and histologic characteristics (see table 1). The treatment and prognosis may overlap for many types of lymphoma. However, there are several types of lymphoma/leukemia and that have significant disparity in prognosis and treatment recommendations. The most common type of lymphoma in dogs is high-grade multicentric lymphoma. Exact prevalence statistics varies from study-to-study but high-grade lymphoma comprises between 70 to 85% of cases diagnosed. This would include diffuse, large B-cell lymphoma and peripheral T-cell lymphoma. These cases typically present with acute enlargement of multiple peripheral lymph nodes +/-spleen or liver involvement. Treatment requires maximum tolerated pulse dosing of chemotherapy. For example, CHOP or single agent IV/or chemotherapy such doxorubicin or lomustine plus steroids. Indolent lymphoma and chronic leukemia comprises remaining 15-30% cases of lymphoma.i,ii Some of the more commonly diagnosed indolent lymphoma/leukemia are small cell lymphoma, T-zone lymphoma, chronic lymphocytic leukemia (CLL), and marginal zone lymphoma. These cases generally present with a more slow, insidious history with sometimes incidental finding of splenomegaly or lymphocytosis +/- anemia or thrombocytopenia. Particular breeds also seem to be overrepresented. For example, golden retrievers comprised majority T-zone lymphoma cases in one report. Another study found small and toy breed dogs and bulldogs to be the most common breeds affected with CLL. Diagnosis Diagnosis of low-grade lymphoma or chronic leukemia is possible with cytology of lymph nodes, blood smear, or splenic aspirate. However, these subtypes are comprised of mostly mature, small lymphocytes. Therefore, it may be difficult for pathologists to rule out reactive lymph node or lymphocytosis from low-grade lymphoma/leukemia. Biopsy of a lymph node or bone marrow can typically confirm diagnosis in these cases. Histology is also the only test that can classify all of the distinct types of lymphoma. Unlike cytology, histology is able to assess the architecture of the lymph node relative to the population neoplastic lymphocytes disrupting normal lymph node anatomy. Histology can also provide the grade based on assessment of architecture, mitotic index, cell morphology, and cell size. Although unable to classify all forms of lymphoma/leukemia, molecular testing can aid in diagnosis of lymphoma/leukemia. PARR and flow cytometry help corroborate diagnosis if it is equivocal based on cytology. Flow cytometry can also distinguish between several of the more clinical distinct forms of lymphoma/leukemia. PARR is a PCR test that looks for similarity (ie clonality) of the DNA sequence that codes for the antigen receptor on B-cell and T-cells. A population of lymphocytes from non-neoplastic lymph node, circulation, effusion, or other lymph tissues should have variety in this DNA sequence. Finding the large majority of the cells with the same DNA sequence indicates lymphoma/leukemia. The primers are specific for B-cell receptor or T-cell receptor so PARR is able to form diagnosis of lymphoma or leukemia and specify B-cell or T-cell. PARR cannot distinguish between different forms of lymphoma or leukemia. Since PARR merely needs DNA if can be performed on blood smears or lymph node smear that are days or weeks old. It can even be performed on previously stained samples. The 56 sensitivity of PARR varies between each laboratory. One study reported PARR sensitivity of 67% and 75% for B-cell and T-cell lymphoma, respectively.iii Concordance between PARR and IHC was 67%.3 Flow cytometry uses soluble, live cell sample, such as aspirated cells put in a buffered solution or whole blood. Sample must be collected and then immediately sent for analysis. Fluorescent antibodies are then used to label cells based type of lymphocytes. Sensors can also measure cell size and complexity. Therefore, flow cytometry can aid in initial diagnosis, determine immunophenotype, and distinguish between several of the different subtypes of lymphoma/leukemia. Specifically, flow cytometry can classify lymphoma as either large cell, B-cell lymphoma (typically high-grade lymphoma), intermediate T-cell (typically high-grade), acute leukemia, or chronic leukemia/low-grade lymphoma. Sensitivity is 91% and 100% for flow cytometry diagnosing B-cell and T-cell lymphoma, respectively.3 Agreement between flow cytometry and IHC is 94%.3 Treatment Establishing diagnosis of low-grade lymphoma or leukemia generally leads to more conservative therapy recommendation. Small cell lymphoma, T-zone lymphoma, and chronic lymphocytic leukemia is treated with metronomic chemotherapy and steroids. First line therapy is chlorambucil 0.2 mg/kg/day for 7-14 days and then 0.1 mg/kg/day indefinitely plus prednisone 1 mg/kg/day for 14 days and then 0.5 mg/kg/day thereafter. Monitoring alone is also acceptable for cases that are clinical well without significant cytopenia. Marginal zone lymphoma is generally found in the spleen lymphoma and possible node enlargement. Regardless of other organ involvement it is treated with splenectomy alone. Prognosis Prognosis is generally better for these forms of lymphoma and leukemia despite more conservative therapy. Outcome for chronic leukemia is perhaps influenced by immunophenotype according to one study. T-cell CLL, the most common cell type, was found to have a 930 day median survival time (MST) in 1 study.4 Meanwhile B-cell CLL has a MST of 480 days, and atypical CLL MST of 22 days.iv T-zone lymphoma has a similarly good long term outcome. MST was 647 days in one report.5 If the same report 40% of dogs were golden retrievers and majority of cases had lymphocytosis with lymphadenopathy.v The latter point perhaps shows stage is of less impactful on prognosis for lowgrade lymphoma. Lastly, marginal zone lymphoma treated with splenectomy had an overall MST of 383 days in 1 report. Dogs diagnosed incidentally had MST of over 1,000 days while dogs with clinical signs attributable to splenic disease had MST of 301 days. Outcome was not affected by use of chemotherapy after surgery, lymph node involvement, anemia, nor hemoabdomen.vi 57 Table 1. Summary of Canine Malignant Lymphoma Revised From the Revised European-American Classification of Lymphoid Neoplasms/ World Health Organization Classification of Lymphoid Neoplasms B Cell Neoplasms Precursor B cell neoplasms Precursor B lymphoblastic leukemia/lymphoma Mature (peripheral) B cell neoplasms B cell chronic lymphocytic leukemia/prolymphocytic Leukemia/small lymphocytic lymphoma B cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B cell lymphoma Plasma cell myeloma/plasmacytoma Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type Nodal marginal zone lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B cell lymphomaa Mediastinal large B cell lymphoma Burkitt’s lymphoma/Burkitt’s cell leukemia Provisional entity: high-grade B cell lymphoma Burkitt’s-likea Primary effusion lymphoma T Cell and Putative Natural Killer Cell Neoplasms Precursor T cell neoplasm Precursor T lymphoblastic Lymphoma/leukemia Mature (peripheral) T cell and natural killer cell neoplasms T cell prolymphocytic leukemia Large granular lymphocyte leukemia (LGL) Aggressive natural killer (NK) cell leukemia Peripheral T cell lymphomas, unspecifieda Adult T cell lymphoma/leukemia Intestinal T cell lymphoma (+enteropathy associated) Hepatosplenic gdT cell lymphoma Subcutaneous panniculitis-like T cell lymphoma Mycosis fungoides/Sezary syndrome Anaplastic large cell lymphoma, T and null cell primary cutaneous type Peripheral T cell lymphoma not otherwise specified Angioimmunoblastic T cell lymphoma Angiocentric T cell lymphoma a Peripheral T cell lymphomas are those that are not otherwise specified (NOS) to a specific subtype by further definition. See PTCL (Fig.3 a-d) 58 ________________________________________________ 1 Valli, V. E., San Myint, M., Barthel, A., Bienzle, D., Caswell, J., Colbatzky, F., et al. (2011). Classification of canine malignant lymphomas according to the World Health Organization criteria. Veterinary Pathology, 48(1), 198–211. 1 Carter RF, Valli VE and Lumsden JH. The cytology, histology and prevalence of cell types in canine lymphoma classified according to the National Cancer Institute Working Formulation. Canadian Journal of Veterinary Research 1986; 50: 154–164. 1 Thalheim, L., Williams, L. E., Borst, L. B., Fogle, J. E., & Suter, S. E. (2013). Lymphoma immunophenotype of dogs determined by immunohistochemistry, flow cytometry, and polymerase chain reaction for antigen receptor rearrangements. Journal of Veterinary Internal Medicine, 27(6), 1509–1516. 1 Comazzi, S., Gelain, M. E., Martini, V., Riondato, F., Miniscalco, B., Marconato, L., et al. (2011). Immunophenotype predicts survival time in dogs with chronic lymphocytic leukemia. Journal of Veterinary Internal Medicine, 25(1), 100–106. 1 Seelig, D. M., Avery, P., Webb, T., Yoshimoto, J., Bromberek, J., Ehrhart, E. J., & Avery, A. C. (2014). Canine T-zone lymphoma: unique immunophenotypic features, outcome, and population characteristics. Journal of Veterinary Internal Medicine, 28(3), 878–886. 1 O'Brien, D., Moore, P. F., Vernau, W., Peauroi, J. R., Rebhun, R. B., Rodriguez, C. O., & Skorupski, K. A. (2013). Clinical characteristics and outcome in dogs with splenic marginal zone lymphoma. Journal of Veterinary Internal Medicine, 27(4), 949–954. 59 Intrahepatic Portosystemic Shunts: Diagnosis and Treatment Advances. Jim Perry, DVM, PhD, Diplomate ACVIM (Oncology), Diplomate ACVS Seattle Veterinary Specialists Seattle, WA Congenital portosystemic shunts are defined as aberrant connections between the portal and central venous systems that result in the delivery of portal blood to the systemic venous system without first being filtered through the liver. The result precludes normal detoxification of portal blood by the liver prior. This shunting also reduces the amount of oxygen and nutrients being received by the liver, which normally supports liver development, growth, and function of the liver itself.1 Congenital portosystemic shunts can occur in two primary forms—extrahepatic and intrahepatic. Extrahepatic shunts, as the name implies, occur between the portal and central venous systems prior to the porta hepitus (entrance of the portal vein into the liver). Examples of extrahepatic portosystemic shunts include direct portocaval shunts, portoazygous shunts, splenocaval shunts, gastrocaval shunts, etc. In contrast, intrahepatic shunts occur when branches of the intrahepatic portal vein (either right, left or central) anastomose to a hepatic vein or directly with the intrahepatic caudal vena cava. Extrahepatic portosystemic shunts are often amenable to open surgical attenuation with good to excellent outcomes, while historically; open surgical treatment of intrahepatic portosystemic shunts has been associated with much higher morbidity and mortality. The purpose of the discussion here will be to focus on the less common, but often more challenging, intrahepatic form and current minimally invasive treatment options. In contrast to their extrahepatic counterparts, which typically occur in small breed dogs (Yorkies, Maltese, Pugs, etc.), intrahepatic shunts most commonly occur in large breed dogs. Dog breeds that have been shown to be overrepresented include the Labrador Retriever, Husky, Irish Wolfhound, and certain herding breeds such as Australian Shepherds. Intrahepatic shunts can also occur in smaller dogs, however, these are much less common than extrahepatic shunts in these breeds. The clinical signs associated with portosystemic shunts often become apparent early in life (<3 months) and are similar regardless of whether the shunt is classified as intrahepatic or extrahepatic. Because intrahepatic shunts often result in a higher degree of shunting, the clinical signs can become apparent earlier in the dogs life compared to dogs with extrahepatic shunts. Clinical signs associated with portosystemic shunts include stunted growth, slow recovery from anesthesia, and signs of hepatic encephalopathy. Signs of hepatic encephalopathy are often subtle initially and non-specific, including anorexia, depression and lethargy, but can become more significant with advancement of the disease to include ataxia, head pressing, circline/pacing, cortical blindness, and even seizures/coma. Urinary tract signs (polakiuria, stranguria and hematuria) secondary to ammonium biurate crystalluria/urolithiasis can also be observed but are more common in slightly older untreated animals. Biochemical and hematological changes seen in dogs with portosystemic shunts are also similar between intra and extrahepatic forms. Such abnormalities seen on routine blood work include non-regenerative microcytic anemia, hypoglycemia, hypocholesterolemia, low BUN, hypoalbuminemia, hypoglycemia, and elevation in liver enzymes. Elevations in pre and post-prandial bile acids are also a hallmark of portosystemic shunting and 1 The normal liver receives 80% of its blood supply and 50% of its oxygen from the portal system. In cases where portosystemic shunting is occurring, the liver relies much more on atrial blood and as a consequence fails to develop appropriately and can lead to fibrosis and ultimate liver failure in addition to the signs associated with portosystemic shunts in general. 60 secondary liver dysfunction. High levels of blood ammonia can be used to support the diagnosis of portosystemic shunting, however the absolute level of blood ammonia does not correlate with the type of shunting, the degree of shunting, or to the severity of hepatic encephalopathy. The suspicion of a portosystemic shunt is suggested by the clinical signs and biochemical changes discussed above, while the diagnosis is confirmed via imaging. Abdominal ultrasonography is an excellent means of diagnosing portosystemic shunting and for classifying whether the shunting is occurring in an extrahepatic or intrahepatic fashion. In cases where ultrasound fails to identify or characterize the shunt, advanced imaging such as nuclear scintigraphy or, now more commonly, CT angiography, can be used. Ideally, CT is also performed prior to any transvenous approach to allow for accurate delineation of the anatomy and for measurement purposes (figure 1). FIGURE 1: CT ANGIOGRAM: FIGURE 1: CT ANGIOGRAM: Prior to advances in percutaneous approaches, intrahepatic shunts where typically either managed medically or through open surgical approaches. Reports evaluating dogs treated with medical management alone typically show survival times ranging from 6-12 months from the time of diagnosis/initiation of medical management to euthanasia/death. Open surgical treatment, when performed successfully can significantly extend these survival times, however, the intra and perioperative mortality using this approach can reach as high as 50 percent. This relatively high mortality rate associated with open surgical approaches, and the advances in interventional radiology, has led to the development of safer, less invasive, percutaneous options as discussed below. Fluoroscopically guided percutaneous transjugular coil embolization (PTCE) has markedly reduced the intraoperative and perioperative complication rates, and early data suggest similar if not better long-term outcomes compared to successful open surgical attenuation/ligation. The percutaneous transjugular approach involves fluoroscopic catheterization of the caudal vena cava and shunt vessel through a 10-12F venous access sheath placed in the jugular vein. Once isolated, a properly sized mesh Nitinol stent (Infiniti Medical) is placed within the lumen of the vena cava such that the stent spans the shunt’s osteum. Placement of the caval stent prevents migration of the soon to be deployed coils from the shunt vessel into the vena cava/systemic circulation. Once the stent is placed, the shunting vessel is re-catheterized and deployment of often multiple thrombogenic coils is performed until ideal portal pressures/pressure changes are achieved as measured intraoperatively. Figures 2A and B show the post-operative placement of both the caval stent and thrombogenic coils within the shunting vessel. 61 FIGURE 2: POST OP STENT AND COIL PLACEMENT Ultimately, the goal of PTCE is similar to that performed for extrahepatic shunt treatment—gradually attenuate the flow of blood through the shunting vessel such that the normal portal system can adapt without the development of portal hypertension. The ideal endpoints for absolute portal pressure following the procedure 62 as well as change in pressure remain unknown, but theoretical intra-operative goals are portal pressure to central venous pressure gradients of 5-10mmHg or maximum changes in portal pressure of 5-6mmHg. A drop in central venous pressure of >1mmHg is also considered a stopping point for further attenuation. Following the procedure, patients are typically monitored in hospital for 1-2 days for clinical signs associated with acute portal hypertension (pain, abdominal distension/ascites, diarrhea, systemic hypotension) and the development of neurological sequelae (seizures, coma). Once home, monitoring is continued as the onset of both portal hypertension and neurological side effects can occur several days to weeks after shunt vessel attenuation. The prognosis when acute portal hypertension or neurological sequaelae develop is very poor. When chronic portal hypertension develops, many dogs can improve with time or can be medically managed as acquired shunts develop. The risk for developing neurological sequelae, specifically seizures, is thought to be reduced by pre-treating dogs with Keppra. Patients are typically started on Keppra at the time of shunt diagnosis along with medications aimed at reducing signs of hepatic encephalopathy (lactulose, metronidazole, amoxicillin, low protein diet) and those that decrease gastric acid secretion (H2 blockers or proton pump inhibitors). Following the procedure, these medications are continued for a minimum of 2 weeks. At that time, the Keppra is tapered and antibiotics/lactulose are discontinued. The low protein diet is transitioned after 8 weeks as long as the patient is doing well. Continuation of a proton pump inhibitor is recommended life long as GI ulceration is a known long-term sequelae of portosystemic shunt attenuation. Bile acids are typically rechecked at the 8 week time point for monitoring purposes. As mentioned above, occasionally a chronic low-grade portal hypertension can occur, especially in cases that have portal vein hypoplasia within other regions of the liver. This chronic portal hypertension can lead to the development of multiple acquired portosystemic shunts as well as ascites and recurrence of signs associated with portosystemic shunting (encephalopathy, urate stones, etc.). When this occurs, there is unfortunately little that can be done other than re-instatement of medical management (lactulose, antibiotics, low protein diet, etc.) and supportive care. Even when this occurs, however, dogs can often live with these signs for months to years while enjoying an overall good quality of life with medical management. As with any “new” technique, many questions remain unanswered with regards to long-term prognosis and factors affecting outcomes. Such questions include: 1) What is the ideal pressure gradient or change between the portal and caval systems after attenuation? 5-6mmHg? Absolute portal pressure <12-18mmHg? 2) How should we monitor “success” or “failure” in these cases? Serial bile acids testing? Recheck ultrasound or CT imaging? Clinical signs only? 3) Should the goal be to eliminate all shunting through the vessel or is some residual shunting OK long term? Should a second procedure be performed to add more coils when shunting persists? Is there a balance between residual shunting and safe portal pressures? 4) What is the optimal age for treatment? 4-6 months? 5) If acquired shunts develop secondary to chronic portal hypertension, how does this effect prognosis? Do these patients have improved quality of life compared to those not treated at all? While we are still building our caseload at SVS, a recent report from Dr. Weisse et al. out of the Animal Medical Center in NY, which reviewed 100 cases, showed good to excellent outcomes in 81% of dogs treated with PTCE. Major intra and post-operative complications occurred in <20% of dogs and the median survival times exceeded 6 years. Similar unpublished findings have been observed at UC Davis with Dr. Culp’s group. Thus far here, all dogs treated have been discharged from the hospital within 24 hours of treatment and none have experienced 63 portal hypertension or recurrence of clinical signs after weaning of medical management. Longer term follow up is currently limited as we just started offering the procedure in 2016. Perhaps the largest hurdle in performing PTCE is cost. The average client cost for the work-up (CT angiogram, initial medical management, blood work, etc.) and procedure (fluoroscopic PTCE and hospitalization) is $8,000$10,000. The hospital costs for the catheters and implants alone often exceeds $4000, making this procedure a difficult “sell” for many clients, especially if they do not have insurance. However, as this procedure hopefully becomes more mainstream, and pet insurance becomes more prevalent, we hope that this procedure will become more available to pets diagnosed with intrahepatic shunts. References and Suggested Reading Bussadori R, Bussadori C, Milan L et al: Transvenous coil embolization for the treatment of single congenital portosystemic shunts in six dogs. Vet J 176:221-226, 2008. Gonzalo-Orden JM, Altonaga JR, Costilla S: Transvenous coil embolization of an intrahepatic portosystemic shunt in a dog. Vet Radiol Ultrasound 41:516-518, 2000. Leveille R, Johnson SE, Birchard SJ: Transvenous coil embolization of portosystemic shunt in dogs. Vet Radiol Ultrasound 44:32-36, 2003. Partington BP, Partington CR, Biller DS, et al: Transvenous coil embolization for treatment of patent ductus venosus in a dog. J Am Vet Med Assoc 202:281-284, 1993. Weisse C, Berent AC, Todd K, Solomon JA, Cope C. Endovascular evaluation and treatment of intrahepatic portosystemic shunts in dogs: 100 cases (2001-2011). J Am Vet Med Assoc. 1;244(1): 78-94, 2014. 64 “Keeping Up with the Flow of Extrahepatic Biliary Surgery” Jessica J. Leeman DVM, DACVS-SA Seattle Veterinary Specialists Kirkland, WA Anatomy & Physiology The extrahepatic biliary system is composed of the hepatic ducts, gallbladder, cystic duct, and the common bile duct (CBD). The CBD enters the major duodenal papilla in dogs and cats, however it is conjoined with the pancreatic duct before entering the papilla in cats. The CBD usually measures approximately 5cm in length and 2-4mm in diameter in an average sized dog. It enters the major duodenal papilla about 1.5-6cm distal to the pylorus; the intramural portion is about 2cm. There are typically 26 hepatic ducts. One of the many functions of the liver is to secrete bile, normally between 600-1000mL/day in people. Bile acids, a component of bile, play an important role in fat digestion by emulsifying the larger fat particles of food into smaller particles so that lipase can act on those particles appropriately. Bile acids aid in the absorption of these digested fat end products through the intestinal mucosal surface by the formation of micelles. Vitamin K is a fat soluble vitamin that requires dietary fat emulsification for absorption by the ileum. Bile also serves as a means for excretion of several waste products, including bilirubin and excess cholesterol, and can bind to endotoxin and bacteria of the small intestine to prevent absorption into the portal circulation. In addition to bilirubin and cholesterol, bile is composed (Table 64-2) of many other molecules and electrolytes. Bile is secreted by the liver in two stages. The initial portion contains large amounts of bile acids, cholesterol, and other organic constituents. It is secreted by hepatocytes. A watery solution of sodium and bicarbonate is added to the bile as it flows through the hepatic ducts, which can increase the volume of bile up to 100%. Bile is secreted continuously, but is mostly stored in the gallbladder until needed in the duodenum to aid in digestion. The maximum volume that the gallbladder can hold is only 30-60mLs, however it is continually absorbing water and electrolytes to concentrate the remaining bile constituents. The secretion of the watery solution from the hepatic ducts is stimulated by secretin of the duodenum to help with neutralization of the acidic chyme. 65 Cholecystokinin from the “I” cells of the duodenum and jejunum stimulates gallbladder contraction and the relaxation of the sphincter of Oddi, mainly in response to fatty foods. Gallbladder contraction is also stimulated by the vagus nerve and enteric nervous system, however to a lesser degree. Pathophysiology Extrahepatic biliary obstruction can be caused by pancreatitis, neoplasia, gallbladder mucocele, cholangitis, and/or cholelithiasis. Less commonly, it has been reported in cases of parasitic infection and diaphragmatic hernias. Biliary mucoceles form due to hypersecretion of mucous within the gallbladder lumen and cause secondary obstruction of the biliary tree. Sheltland sheepdogs and dogs diagnosed with hyperadrenocorticism or hypothyroidism are more likely to develop gallbladder mucoceles. The underlying mechanism is incompletely understood. Gall stones in people form secondary to an increased concentration of bile cholesterol. High fat diets and low grade inflammation/infection have been shown to cause precipitation of gall stones. Gall stones are primarily composed of calcium bilirubinate in dogs and calcium carbonate in cats. The cause of gall stones in small animals is unknown. Consequences to biliary obstruction, primarily reported in surgical patients, include hypotension, decreased myocardial contractility, acute renal failure, gastrointestinal hemorrhage, and delayed wound healing. The exact mechanism by which these complications occur remains unclear, however it is thought to be related to the absence of bile acids in the intestines leading to bacterial overgrowth and systemic endotoxin absorption. Concurrently, the liver’s reticuloendothelial (immune) system (RES) is downregulated during this time. Coagulopathies tend to occur secondary to decreased absorption of dietary vitamin K from the small intestines, which is responsible in helping the liver convert procoagulation factors II, VII, IX, X into their active forms. Since factor VII has the shortest half-life of the routinely measured coagulation factors in dogs and cats, it would be expected that prothrombin time (PT) would be prolonged prior to partial thromboplastin time (PTT). Prolongation of both values have been associated with a poorer prognosis. Bile peritonitis occurs when there is release of bile into the peritoneum from the biliary tree. It may be diagnosed when the bilirubin of the peritoneal fluid is twice that of the serum concentration. This may occur as a sequelae to biliary obstruction because of dehiscence, failure of ligatures, or pressure necrosis of the biliary tree’s wall. Free abdominal bile salts cause inflammation, hemolysis, and tissue necrosis. Their hyperosmolality lead to significant fluid shifts from the vascular space into the abdominal cavity, which causes dehydration and hypovolemic shock. Bile is normally sterile, however it can become infected by ascending microbes, bacterial translocation within the intestines, or colonization by 66 resident hepatic anaerobes. Cultured bacteria in cases of cholecystitis and bactibilia have included Klebsiella spp, Clostridia spp, Corynebacterium spp, Bacteroides spp, Streptococcus faecalis spp, Peptostreptococcus anaerobius, and Escherichia coli. If an infection is present, septic bile peritonitis often carries a poorer prognosis. There is a 27-45% survival rate for dogs with septic bile peritonitis and an 87-100% survival rate for dogs with a sterile process. Case Evaluation & Stabilization Patients presenting with biliary obstruction with or without bile peritonitis often have non-specific clinical signs, such as vomiting, diarrhea, lethargy, anorexia. However, icterus will likely prompt a closer evaluation of pre-hepatic, hepatic, and post-hepatic etiologies. Biochemical abnormalities often include hyperbilirubinemia, hypoalbuminemia, increased cholesterol, and increased liver enzymes. Hematologic abnormalities often include an inflammatory leukocytosis and possible hemoconcentration. Prolongation of coagulation times are also often appreciated as well. Less commonly, a fluke infestation may be identified by fecal evaluation. Abdominal ultrasonography is the best imaging modality for evaluating the extrahepatic biliary tree. Abnormal ultrasound findings may include evidence of biliary dilation, gallbladder mucocele, pancreatitis, neoplasia, and cholelithiasis. Ductule distention may be detected as early as 4 hours after experimental biliary occlusion. Abdominal radiographs typically do not reveal any specific findings consistent with biliary obstruction. However, radiopaque choleliths in 50% of dogs and 80% of cats and mineralization of the hepatic ducts may be appreciated with survey radiographs. The presence of these findings may represent a cause of the obstruction, however they may also be an incidental finding. Other imaging modalities performed less commonly for biliary obstruction include scintigraphy, CT/MRI cholangiopancreatography, and endoscopic retrograde cholangiopancreatography. The latter two modalities are more common in human medicine, however endoscopic retrograde cholangiography with biliary stenting has been recently described in two dogs. Patients with obstructive biliary disease are often hypovolemic and hypotensive due to significant fluid shifts. They should be resuscitated using crystalloids and/or colloids, and electrolyte abnormalities should be supplemented accordingly. Vitamin K may be administered for the proper function of its dependent clotting factors II, VII, IX, and X. In the event there is prolongation of the coagulation times due to the relative vitamin K deficiency, fresh frozen plasma may be administered for supplementation. Surgery & Outcome Cholecystectomy is the most common biliary procedure performed. Indications for this procedure include mucocele formation, necrotizing cholecystitis, cholelithiasis, gallbladder neoplasia, and severe gallbladder trauma. The procedure may be performed by laparoscopy or laparotomy. After dissection from the adjacent hepatic parenchyma, the gallbladder is excised at the level of the cystic duct. Care must be taken to preserve the nearby hepatic artery. The patency of the common bile duct is checked prior to ligation by passing a small red rubber catheter normograde through the lumen of the cystic duct and major duodenal papilla. A red rubber catheter may also be passed retrograde through the major duodenal papilla via duodenotomy. The cystic duct is then closed using suture material or vascular clips/staples. The excised gallbladder is then submitted for culture and histopathology. Conversion rate from laparoscopic to open cholecystectomy is 30%, and has occurred in cases where there has been the inability to ligate the cystic duct, evidence of gallbladder rupture, leakage from the cystic duct during dissection, and cardiac arrest. Potential complications for both procedures include bile leakage from failure of cystic duct ligatures, hemorrhage secondary to failure of cystic artery ligations, or from damage to the liver parenchyma during gallbladder dissection, and failure to document CBD patency prior to cholecystectomy. Mortality rate is 22-40% following cholecystectomy for biliary mucoceles. Post-operative hypotension and hyperlactatemia have been associated with poorer outcomes. 67 Cholecystoenterostomy is a rerouting procedure where a stoma is created between the gallbladder and small intestines, either the duodenum or jejunum, to redirect flow of the bile from the CBD to the newly created stoma. The procedure may be performed by laparoscopy or laparotomy, however the laparoscopic approach is currently not recommended in small animals due to a high complication rate. About 75% of cases were found to leak when a laparoscopic cholecystoduodenostomy was performed in a group of canine cadavers. Cholecystoenterostomy is typically performed when the primary cause of the obstruction cannot be alleviated or the alleviation risks outweigh the benefits, thus increasing the patient’s morbidity. Such cases include cholelithiasis or neoplasia of the CBD. Another indication for the procedure is when a gastrojejununostomy (Billroth II) is performed. In these cases, the duodenum is excised along with the pancreas and major duodenal papilla. A cholecystoduodenostomy is always preferred over cholecystojejunostomy because it is more physiologic. Gastric acid secretion is inhibited by the presence of bile within the duodenum. If this inhibitory feedback is lost, gastric acid oversecretion may occur, resulting in an elevated incidence of ulcer formation. Bile also contains bicarbonate that is responsible for neutralizing gastric contents entering the duodenum and is important in fat digestion as previously noted. During cholecystoenterostomies, the gallbladder may be mobilized from the hepatic fossa to reduce tension at stoma site. The liver parenchyma may bleed, but hemostasis is generally achieved easily using direct pressure or topic hemostatic agents. Four simple continuous suture lines are created in total during the procedure: two on each side of the stoma. The procedure may also be performed using an EndoGIA stapling device. The stomas should be created as long as possible, which is typically around 4cm, because there will be significant contracture of the stoma during the healing period. Generally, the stoma will decease about 50% during the healing period. If a healed stoma is <2.5cm, there is risk for obstruction and ascending cholangiohepatitis. Additional complications associated with this procedure include hemorrhage, dehiscence, and enteric reflux into the biliary tree. Choledochal stenting is most commonly performed for treatment of temporary conditions, such as when pancreatitis or cholangiohepatitis cause obstruction of the CBD. It may also be performed in cases where the CBD is damaged and primary repair is indicated. Stenting following primary repair of the CBD or choledochotomy allows the stent to support the repair during the healing phase. Red rubber catheters are commonly used for stenting of the CBD and the catheter size will vary depending on the size of the animal. The largest stent that does not fill the CBD lumen should be chosen. Approximately 2-4cm of the catheter should remain within the duodenal lumen for anchoring using an absorbable monofilament suture for temporary use or non-absorbable monofilament suture for permanent use. Spontaneous passage of the catheter is common, however retrieval of the stent may be performed via endoscopy up to several months following resolution of the underlying disease. Choledochal stenting is generally performed via laparotomy, however there are few reports of endoscopically placed biliary stents. Re-obstruction and ascending cholangiohepatitis are two complications that may follow choledochal stenting. Sphincter-altering procedures are performed when a cholelith is lodged in the terminal CBD adjacent to the major duodenal papilla. This procedure is performed by incising a portion of the intramural portion of the CBD and removing the stone within the duodenum. Choledochotomy is generally not performed due to the small size of the CBD and the significant risk of dehiscence and stricture formation. The wall of the CBD is generally thin and extremely friable in diseased states. Cholecystotomy is a rarely indicated procedure. It may be performed if choleliths need to be removed, however a cholecystectomy is typically performed to prevent recurrence of stones. Cholecystotomy may also be performed to gain access to the gallbladder lumen to check patency of the CBD prior to performing a cholecystoenterotomy, obtain full-thickness biopsy samples, or obtain mucosal samples 68 for culture. Closure is performed using an absorbable monofilament in a single- or double-layer closure with full-thickness bites to ensure submucosa incorporation. Potential complications include recurrence of cholelith formation and incisional dehiscence. Post-operative Care Anecdotally, most patients remain hospitalized for about 3-5 days following surgery. Their vitals (HR, RR, temp, BP) are monitored closely throughout this time. Serial labwork is performed throughout their stay for monitoring of hematologic and biochemical abnormalities. Serial coagulation profiles are also monitored as indicated. Patients receive intravenous fluids (crystalloids, colloids), analgesia (fentanyl, lidocaine), antibiotics (ampicillin, enrofloxacin, metronidazole), Denamarin, and urosodial. Vitamin K and fresh frozen plasma are administered as indicated. Feeding tubes and abdominal drains are also placed on a case by case basis. Prognosis Prognosis associated with extrahepatic biliary tract disease is considered guarded in most cases. Reported mortality rates for dogs and cats are 20-40% and 40-60%, respectively. Those with early recognition and diagnosis of extrabiliary tract obstruction, along with surgical intervention in a timely manner, may have a much better outcome. References Berent A, Weisse C, Schatter M, et al. Initial experience with endoscopic retrograde cholangiography and endoscopic retrograde biliary stenting for treatment of extrahepatic bile duct obstruction in dogs. J Am Vet Med Assoc 2015;246:436446. Besso JG, Wrigley RH, Gliatto JM, et al. Ultrasonographic appearance and clinical findings in 14 dogs with gallbladder mucocele. Vet Radiol Ultrasound 2000;41:261-271. Guyton AC and Hall JE. Texbook of Medical Physiology. Philadelphia:Elsevier-Saunders, 2006. Lawrence YA, Ruaux CG, Nemanic S, et al. Characterization, treatment, and outcome of bacterial cholecystitis and bactibilia in dogs. J Am Vet Med Assoc 2015;246:982-989. Malek S, Sinclair E, Hosgood G, et al. Clinical findings and prognostic factors for dogs undergoing cholecystectomy for gallbladder mucocele. Vet Sure 2013;42:418-426. Martin-Portugues ID, Matos-Azevedo AM, Sans SE, et al. Laparoscopic cholecsytoduodenostomy in dogs: canine cadaver feasibility study. Vet Surg 2016;45:34-40. Mehler SJ. Complications of extrahepatic biliary surgery. Vet Clin Small Anim 2011;41:949-967. Pike FS, Berg J, King NW, et al. Gallbladder mucocele in dogs: 30 cases (2000-2002). J Am Vet Med Assoc 2004;224:1615-1622. Scott J, Singh A, Mayhew PD, et al. Perioperative complications and outcome of laparoscopic cholecystectomy in 20 dogs. Vet Surg 2016;45:49-59. Tobias KM and Johnston SA. Veterinary Surgery Small Animal. St. Louis:Elsevier-Saunders, 2012. 69 Updates for Mitral Valve Disease Mikaela Mueller, DVM, DACVIM (Cardiology) Seattle Veterinary Specialists Kirkland, WA Introduction - Degenerative Valve Disease Degenerative valve disease is the most common cardiac condition seen in canine medicine. A genetic predisposition has been identified in multiple breeds, including Cavalier King Charles Spaniels (CKCS), Chihuahuas, Miniature Poodles, Dachshunds, Miniature Schnauzers, Whippets, Shih Tzus, Maltese, Cocker Spaniels, and Pomeranians. While characteristically seen in small-breed dogs, it is also seen in some large breed dogs. The spongiosa layer of the mitral valve becomes progressively and irregularly thickened, leading to poor coaptation of the leaflet tips. At the same time, the chordae tendinae become elongated and sometimes break, leading to progressive prolapse of the leaflets. These changes are most notable in the mitral valve, but frequently affect multiple valves of the heart. As the condition advances, there is progressive leaking of the mitral valve. Decreased forward flow leads to fluid retention by the kidneys, causing increased circulatory volume and compensatory enlargement of the left side of the heart. As the pressure in the left side of the heart rises, fluid and pressure back up into the pulmonary circulation (post-capillary pulmonary hypertension), eventually leading to pulmonary edema (congestive heart failure, CHF). The ACVIM Consensus classification system identifies the following stages of degenerative valve disease: A - Patients at high risk for developing heart disease (genetic predisposition), but with no current identifiable lesions. B - Patients with structural heart disease who have never had clinical signs of heart failure - B1 - Patients with structural heart disease who have no radiographic or echocardiographic evidence of cardiac remodeling in response to chronic valvular disease (cardiac enlargement). - B2 - Patients with structural heart disease with radiographic and/or echocardiographic evidence of left-sided heart enlargement, indicating hemodynamically significant valve regurgitation. C - Patients with past or current clinical signs of congestive heart failure. D - Patients with end-stage disease and clinical signs of CHF that are refractory to standard therapy. 70 Traditional treatment of CHF revolves around 5 main approaches: 1. Preload reduction (furosemide, torsemide, hydrochlorothiazide) - Diuretics reduce circulatory volume to reduce left-sided filling pressure. 2. Afterload reduction (amlodipine, hydralazine, nitroglycerin/nitroprusside) - Decreased systemic blood pressure (vasodilation) encourages forward blood flow, resulting in decreased left atrial pressure. 3. RAAS inhibition (ACE-inhibitors, spironolactone) - RAAS inhibition decreases fluid retention, helps to prevent cardiac fibrosis and arrhythmogenesis, and has minimal decrease in systemic blood pressure. 4. Inotropic support (pimobendan, dobutamine) - Improve contractility (and dilate systemic circulation, in the case of pimobendan) to improve forward flow, increasing circulation to organs and reducing left atrial pressure. 5. Normalize heart rate and rhythm by treating arrhythmias to maximize cardiac output. What about before the onset of CHF? The EPIC Trial In the past, pre-CHF treatment of degenerative valve disease has involved the “watch and wait” approach, or, often, the use of ACE-inhibitors. Several studies have been conducted to assess the efficacy of ACE-inhibitors in delaying the onset of CHF. So far, we’ve shown a trend towards increased time to onset of clinical signs, however a statistically significant increase in time has not been proven. The results of the EPIC trial were announced at ACVIM in 2016, and later published in November in JVIM. In the trial, pimobendan (Vetmedin) was started prior to the onset of CHF in dogs with cardiomegaly due to degenerative valve disease. Results were spectacular, showing a 15-month increase in the time to the primary endpoint (onset of CHF, cardiac-related death, or euthanasia), which was a 60% increase in the amount of time that patients spent in the asymptomatic stage (B2). Additionally, dogs who were started on pimobendan when diagnosed with cardiomegaly lived 10% longer than dogs who did not start pimobendan until the onset of CHF of later. The results of the EPIC trial are remarkable enough that it rapidly launches pimobendan as the standard of care for patients with cardiomegaly due to degenerative valve disease. However, chronic administration of pimobendan has its disadvantages. All medications can have side effects, and some patients show gastrointestinal side effects to pimobendan. Additionally, pimobendan is currently a fairly expensive medication, particularly for large-breed dogs. Vetmedin’s patent expired in September 2015, however we have yet to develop a more price-effective generic formulation in the USA. Many dogs remain in stage B2 for years, which can add up to a large amount of money. Many patients with degenerative valve disease would never reach stage C, succumbing instead to different disease processes that often accompany advanced age. It is our job as veterinarians to help owners to make the best decision for their pet and family of whether or not to start pimobendan. 71 Cardiac Biomarkers in Degenerative Valve Disease Cardiac biomarkers, specifically natriuretic peptides (NT-proBNP, NT-proANP) and cardiac troponins (cTnI) have gained usefulness in the clinical setting. NT-proBNP has become more useful since it is now available in external laboratory panels as well as cage-side tests. Increased NT-proBNP is an indicator of cardiomyocyte stretch (increased chamber pressure). A study performed in 2012 (the PREDICT cohort study) showed that NT-proBNP increases most significantly in the time period leading up to the onset of CHF, and a level of 1500 pmol/L was found to be an independent risk factor for the development of CHF. Another study by Eriksson et al. found that patients with NT-proANP >1000 pmol/L have a median of 11 months until the onset of CHF, while patients with NT-proANP < 1000 pmol/L have a median of 54 months until the onset of CHF. NT-proBNP is not a substitute for conventional diagnostics, but it has clinical uses as a supportive measurement, including screening for clinically significant heart disease in patients with heart murmurs, prior to anesthesia and in the evaluation of the coughing dog with a concurrent heart murmur. Cardiac troponin (such as cTnI) are sensitive and specific markers of myocardial injury, and have been shown to be increased in canine patients who are at risk for cardiac-related death. Future work is needed to determine if cardiac troponins can be effectively used to guide treatment. Fixing Broken Hearts - Surgical Options There are currently multiple procedures and devices in clinical trials for surgical correction of advanced degenerative valve disease. One of these experimental devices is the MitralSeal, which is being developed through a collaborative effort between Colorado State University and Avalon Medical. The MitralSeal is a transcatheter mitral valve replacement device that is placed using a hybrid procedure. A thoracotomy is performed and the device is deployed via a catheter through the left ventricular apex using radiographic or echocardiographic guidance. The device is placed on the left atrial surface of the mitral valve and tethered externally against the left ventricle. The Mitrex device is another experimental device that is being developed by Infiniti Medical. It is an external annuloplasty device, placed by a team of a surgeon and a cardiologist. The device is sized with echocardiographic guidance during the procedure with the goal of reducing the mitral valve annulus by external pressure, increasing coaptation of the thickened mitral valve leaflets to reduce mitral valve regurgitation. The device is placed around the mitral valve on the epicardial surface of the heart and anchored to the left ventricle. Results of the 6-month pre-clinical trial have so far been promising. Both of these devices are examples of devices that are being developed with the goals of producing a simple and cost-effective solution, with potential availability to patients all over the world. Pending clinical trials, it is promising that these devices, or other similar devices, may provide options that are accessible to our patients since they do not require the specialization of cardiopulmonary bypass and cardioplegia. While procedures such as placement of the MitralSeal or the Mitrex devices are in the experimental stages, mitral valve repair surgery is already an option for patients with degenerative valve disease. It is a highly specialized procedure involving a team of veterinarians to perform the surgery, run anesthesia, and manage cardiopulmonary bypass (CPB). The patient is cooled under general anesthesia to reduce cellular metabolism. The patient is then placed on CPB via the carotid artery and jugular vein. Cardioplegia is maintained throughout the procedure to aid the surgeon and to reduce cardiac metabolism while the patient is on CPB. The mitral valve is repaired via a left atrial approach. Depending on the changes present in each case, mitral valve repair is 72 primarily accomplished by artificial chordal replacement and circumferential mitral annuloplasty. This procedure has been perfected by Dr. Masami Uechi and his surgical team at the JASMINE (Japan Animal Specialty Medical Institute) Veterinary Cardiovascular Medical Center, with a published 94% success rate. Dr. Uechi and his team perform mitral valve repair from their medical center in Japan, and travel bimonthly to France and Singapore for additional cases. Mitral valve repair is an extravagant treatment, but it is curative and has a high success rate. It is a great option to consider for patients with stage B2 and early stage C degenerative valve disease who have owners with no financial constraints. References • Atkins CE, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med 2009;23(6):1142-50. • Atkins CE, et al. Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency (VETPROOF). J Am Vet Med Assoc 2007;231(7):1061-9. • BENCH (Benazepril in Canine Heart Disease) Study Group. The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, longterm clinical trial. J Vet Cardiol 1999;1(1):7-18. • Boswood A, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: The EPIC study - A randomized clinical trial. J Vet Intern Med 2016;30(6):1765-79. • Eriksson AS, et al. Increased NT-proANP predicts risk of congestive heart failure in Cavalier King Charles Spaniels with mitral regurgitation caused by myxomatous valve disease. J Vet Cardiol 2014;16(2):141-54. • Kvart C, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. J Vet Intern Med 2002;16(1):80-88. • Langhorn R and Willesen JL. Cardiac troponins in dogs and cats. J Vet Intern Med 2016;30(1):36-50. • Reynolds,CA, et al. Prediction of first onset of congestive heart failure in dogs with degenerative mitral valve disease: The PREDICT cohort study. J Vet Cardiol 2012;14(1):193-202. • Sargent J, et al. Echocardiographic predictors of survival in dogs with myxomatous mitral valve disease. J Vet Cardiol 2015;17(1):1-12. • Uechi M. Mitral valve repair in dogs. J Vet Cardiol 2012;14(1):185-92. • Uechi M, et al. Mitral valve repair under cardiopulmonary bypass in small-breed dogs: 48 cases (2006-2009). J Am Vet Med Assoc 2012;240(10):1194-201. 73