Today's Veterinary Practice, March 2017 by davidpsu

IN THIS ISSUE 20 URETHRAL INCOMPETENCE 66 SURGICAL APPROACH TO EAR DISEASE 74 FEVER OF UNKNOWN ORIGIN IN CATS

Diets and the Dermis

MARCH/APRIL 2017 VOLUME 7, NUMBER 2

FROM ITCHY AND ANGRY

CYTOPOINTâ&#x201E;˘ provides fast, effective relief that helps improve the long-term quality of life for dogs with atopic dermatitis and their families1

Indication:

CYTOPOINT aids in the reduction of clinical signs associated with atopic dermatitis in dogs. References: 1. Data on file, Study Report No. C863R-US-12-018, Zoetis LLC. 2. Gonzales AJ, Humphrey WR, Messamore JE, et al. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol. 2013;24(1):48-53. doi:10.1111/j.1365-3164.2012.01098.x. 3. Data on file, Study Report No. C362N-US-13-042, Zoetis LLC. 4. Data on file, Study Report No. C961R-US-13-051, Zoetis LLC.

TO IZZY AND ANGIE

TARGETED

WORKS FAST AND LASTS

SAFE

Targets and neutralizes interleukin (lL)-31, a key itch-inducing cytokine in atopic dermatitis2

Begins working within 1 day and delivers 4 to 8 weeks of relief* from the clinical signs of atopic dermatitis; in-office administration ensures compliance1

Safe for dogs of all ages, even those with concomitant diseases, and can be used with many common medications3,4

To learn more, please visit www.CYTOPOINT.com *Repeat administration every 4 to 8 weeks as needed in the individual patient.1 All trademarks are the property of Zoetis Services LLC or a related company or a licensor unless otherwise noted. ÂŠ 2016 Zoetis Services LLC. All rights reserved. CYT-00107

MARCH/APRIL 2017

VOLUME 7, NUMBER 2

An official journal of the NAVC, Todayâ&#x20AC;&#x2122;s Veterinary Practice is the trusted source for peer-reviewed clinical information in small animal veterinary medicine. Our goal is to enhance knowledge and encourage

Editor in Chief

confidence, inspiring

Simon R. Platt

the highest quality of

BVM&S, MRCVS, DACVIM (Neurology) & DECVN University of Georgia College of Veterinary Medicine SRPlatt@NAVC.com

veterinary care. As an NAVC publication, our audience has access to world-class continuing professional

NAVC BOARD OF DIRECTORS PRESIDENT Gail Gibson, VMD IMMEDIATE PAST PRESIDENT Melinda D. Merck, DVM PRESIDENT-ELECT K . Leann Kuebelbeck, DVM, DACVS

development developed for

VICE PRESIDENT Cheryl Good, DVM

the global veterinary health care community.

TREASURER Laurel Kaddatz, DVM DIRECTORS Paige Allen, MS, RVT Harold Davis, Jr, BA, RVT, VTS (Emergency & Critical Care) (Anesthesia & Analgesia)

An official journal of the

Chief Executive Officer, NAVC Better care through knowledge

Thomas M. Bohn, MBA, CAE TBohn@NAVC.com

Cheryl Good, DVM

Sally Haddock, DVM

Bob Lester, DVM

Your trusted vaccines, now from

minimalism can be magniFicent The ULTRA line of 0.5 mL vaccines* offers: Effective protection with minimal injection volume The opportunity to provide a better vaccine experience And that’s a beautiful thing

The label contains complete use information, including cautions and warnings. Always read, understand and follow label and use directions. *The ULTRA vaccine line includes ULTRATM Duramune®, ULTRATM Fel-O-Vax®, and ULTRATM HybridTM. Duramune®, Fel-O-Vax®, HybridTM , ULTRA™, Elanco and the diagonal bar are trademarks owned by or licensed to Eli Lilly and Company, its subsidiaries or affiliates. © 2017 Eli Lilly and Company, its subsidiaries or affiliates. USCAHMUL02033

MARCH/APRIL 2017

VOLUME 7, NUMBER 2

EDITORIAL ADVISORY BOARD SENIOR VICE PRESIDENT OF SALES & PUBLISHING

P. Jane Armstrong

Laura C.S. Walker

LWalker@NAVC.com

DVM, MS, MBA, DACVIM (SAIM) University of Minnesota College of Veterinary Medicine

PUBLISHER

Nick Paolo, MS, MBA NPaolo@NAVC.com

EXECUTIVE EDITOR

Robin Henry

RHenry@NAVC.com

Mark Cofone

MANAGING EDITOR

VMD, DACVS Veterinary Specialty Center Wilmington, Delaware

Jackie D’Antonio

JDantonio@navc.com DIRECTOR OF SALES

Renee Luttrell

610.558.1819 • RLuttrell@NAVC.com DIRECTOR OF AUDIENCE DEVELOPMENT

Sheila Grosdidier

SReynolds@NAVC.com

RVT, PHR Veterinary Management Consultation Evergreen, Colorado

Sondra Reynolds

SENIOR ART DIRECTOR

Michelle Taylor

MTaylor@NAVC.com ART DIRECTOR

David Beagin

Garret Pachtinger

ASSISTANT EDITOR

VMD, DACVECC Veterinary Specialty & Emergency Center Levittown, Pennsylvania

DBeagin@NAVC.com

Julie Butler

STAFF WRITER

Megan Cox

STAFF EDITORS

Jennifer DiSanto; Suzanne B. Meyers; Lisa Wirth, VMD

Michael Schaer DVM, DACVIM, DACVECC University of Florida College of Veterinary Medicine

GRAPHIC DESIGNER

Courtney Ballauer

WARRANTIES, LIMITATIONS. Except as expressly set forth herein, Eastern States Veterinary Association, Inc (NAVC) makes no warranties whatsoever, express, implied, or statutory. NAVC specifically disclaims any implied warranty of merchantability or fitness for a particular purpose. In no event will NAVC be liable to you or any third party for any indirect, punitive, special, incidental, or consequential damages (including loss of profits, use, data, or other economic advantage), however it arises, even if NAVC has previously been advised of the possibility of such damage. All rights reserved. No part of this publication may be reproduced in any form without written permission from the publisher. Entire contents ©2017 Eastern States Veterinary Association, Inc (NAVC).

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Change Name/Address or Cancel. Please use online form at tvpjournal.com or contact us by phone, fax, or email subscriptions@CDS1976.com.

Email subscription form to subscriptions@CDS1976.com or fax to 630.739.9700. Free subscriptions only to qualifying subscribers.*

Please provide the ID number (directly above your name on label) for positive identification. If the ID number is not available or legible, provide name and address as it appears on the label to allow identification of the subscription.

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*Qualifying Subscribers: Veterinarians, members of the veterinary health care team, veterinary school faculty, veterinary students, and other professionals allied to the field. Eastern States Veterinary Association, Inc (NAVC) reserves the right to determine eligibility for a free subscription.

YOU’VE GOT HER BACK. VETMEDIN® HAS HER HEART.

No other canine CHF drug offers the same level of research and support as Boehringer Ingelheim Vetmedica, Inc. Industry-trusted VETMEDIN gives dogs with congestive heart failure (CHF) better days and longer lives.1 It’s backed by years of groundbreaking canine cardiology research. And only VETMEDIN offers free tools that educate your clients to recognize the signs of CHF faster—which can lead to treatment sooner. Contact your Boehringer Ingelheim Vetmedica, Inc. representative today for a heart to heart about VETMEDIN. Reference: 1. Lombard CW, Jöns O, Bussadori CM; for the VetSCOPE Study. Clinical efﬁcacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc. 2006;42(4):249–261.

IMPORTANT SAFETY INFORMATION: Use only in dogs with clinical evidence of heart failure. The safety of VETMEDIN has not been established in dogs with asymptomatic heart disease or in heart failure caused by etiologies other than atrioventricular valvular insufficiency or dilated cardiomyopathy. Please refer to the package insert for complete product information or visit www.vetmedin.com. VETMEDIN is a registered trademark of Boehringer Ingelheim Vetmedica GmbH, licensed to Boehringer Ingelheim Vetmedica, Inc. © 2016 Boehringer Ingelheim Vetmedica, Inc. VET0515009

17136

FEATURES 20 RACE-APPROVED CE CREDIT ARTICLE

Urethral Incompetence in Dogs: Updates in Management Julie K. Byron, DVM, MS, DACVIM Urethral incompetence is the most common reason for urinary incontinence in dogs. Management of these patients can start out as being relatively straightforward; however, many dogs need adjustments in their therapy as they age or develop additional health concerns. To see the CE test for this article, please visit tvpjournal.com.

FEATURE

Surgical Approach to External and Middle Ear Disease in the Dog and Cat Mark Cofone, VMD, DACVS Diseases of the external and middle ear are common problems in both the dog and cat. Surgery may become the most effective recourse for treatment. This article discusses prediagnostic testing and the 4 main surgical approaches to external and middle ear diseases.

FEATURE

Uncovering the Cause of Fever in Cats Kenneth R. Harkin, DVM, DACVIM (Small Animal Internal Medicine) Fever in cats can be frustrating to clinicians when the cause remains elusive after a thorough workup. In these cases, it may be helpful to categorize the animalâ&#x20AC;&#x2122;s risk for various diseases based on specific parameters, including age, environment, and number of cats in the household.

10 11 16 29

ADVERTISER INDEX NAVC PERSPECTIVES TODAYâ&#x20AC;&#x2122;S VETERINARY NEWS NEW PRODUCT GALLERY

TABLE OF CONTENTS

To read this issue online, visit tvpjournal.com

THAN WHAT’S ON THE SURFACE. DIAGNOSE BELOW THE GUM LINE WITH SCHICK 33 With more pet owners demanding high-quality veterinary dental care, it makes sense to add the Dentsply Sirona digital x-ray system with Schick 33 and HELIODENTPLUS to your practice. Together these products provide an easy solution for high-resolution intraoral radiography and the best diagnostic capabilities. Contact your Patterson Veterinary rep or learn more at vet.schickbysirona.com For more information: VetSales@sirona.com or 877-SCHICKVET

COLUMNS 13 EDITOR’S NOTE

Grief: The Secret Among Us? Simon R. Platt, BVM&S, MRCVS, DACVIM (Neurology) & DECVN

ACVN NUTRITION NOTES

Diets and the Dermis: Nutritional Considerations in Dermatology

CONSIDER THIS CASE

An Uncontrolled Diabetic Dog

104

Focus on Canine Heartworm Disease

111

VET REPORT VITALS

Dermatology Diagnostics: Cutaneous Cytology HOW I TREAT…

Separation Anxiety An Interview with Dr. Terry Curtis

Molly D. Savadelis

DERMATOLOGY DETAILS

Chris Reeder, DVM, DACVD

Ann Della Maggiore, DVM, DACVIM

AHS HEARTWORM HOTLINE

Small Animal Abdominal Ultrasonography: The Spleen Elizabeth Huynh, DVM, and Clifford R. Berry, DVM, DACVR

Justin Shmalberg, DVM, DACVN, DACVSMR

IMAGING ESSENTIALS

119

First Look: The Banfield VET Report

FOCUS ON PHARMACOLOGY

Use of Antibiotics for the Urinary Tract JD Foster, VMD, DACVIM

128 ASPCA PRACTICAL TOXICOLOGY

How to Be Prepared for Most Toxic Exposures in Dogs and Cats Laura Stern, DVM

Correction In Table 2 of the January/February 2017 article “Treatment Guidelines for Chronic Kidney Disease in Dogs and Cats,” the canine urine protein:creatinine ratio for the borderline proteinuric category was incorrectly listed as 1.4–2. The correct range is 0.2–0.5.

Today’s Veterinary Practice does not, by publication of ads, express endorsement or verify the accuracy and effectiveness of the products and claims contained therein. The publisher, Eastern States Veterinary Association, Inc (NAVC), disclaims any liability for any damages resulting from the use of any product advertised herein and suggests that readers fully investigate the products and claims prior to purchasing. The opinions stated in this publication are those of the respective authors and do not necessarily represent the opinions of the NAVC nor its Editorial Advisory Board. NAVC does not guarantee nor make any other representation that the material contained in articles herein is valid, reliable, or accurate; nor does the NAVC assume any responsibility for injury or death arising from any use, or misuse, of same. There is no implication that the material published herein represents the best or only procedure for a particular condition. It is the responsibility of the reader to verify the accuracy and applicability of any information presented and to adapt as new data becomes publicly available. Today’s Veterinary Practice (ISSN 2162-3872 print and ISSN 2162-3929 online) is published bi-monthly (Jan/Feb, Mar/Apr, May/June, Jul/Aug, Sept/ Oct, Nov/Dec; 6x per year) by North American Veterinary Conference, 37 Paul Lane, Glen Mills, PA 19342. Periodicals postage paid at Glen Mills, PA 19342 and additional mailing offices. POSTMASTER: Send all UAA to CFS (See DMM 507.1.5.2); NON-POSTAL AND MILITARY FACILITIES: send address corrections to CDS/Today’s Veterinary Practice, 440 Quadrangle Drive, Ste E, Bolingbrook, IL 60440.

TABLE OF CONTENTS

To read this issue online, visit tvpjournal.com

AMOXICILLIN TRIHYDRATE AND CLAVULANATE POTASSIUM TABLETS DOGS: Indicated in the treatment of periodontal and skin and soft tissue infections such as wounds, abscesses, cellulitis, and superficial/juvenile and deep pyoderma due to susceptible strains of bacteria. CATS: Indicated in the treatment of urinary tract infections (cystitis) and skin and soft tissue infections such as wounds, abscesses, and cellulitis/dermatitis due to susceptible strains of bacteria. Backed by the newly combined Veterinary Technical Services and Sales Support Teams of both Dechra and Putney. Available in 62.5 mg, 125 mg, 250 mg, and 375 mg tablets supplied in foil strip packs. Each carton holds 15 foil strip packs with 14 tablets per strip (210 tablets per carton).

PUTNEY IS NOW PART OF DECHRA VETERINARY PRODUCTS

Ask your Dechra or distributor representative for further information or visit www.dechra-us.com. As with all drugs, side effects may occur. Amoxicillin Trihydrate and Clavulanate Potassium Tablets contain a semisynthetic penicillin (amoxicillin) and have the potential for producing allergic reactions. This product should not be used in animals with a history of an allergic reaction to any of the penicillins or cephalosporins. If an allergic reaction occurs, administer epinephrine and/or steroids. Refer to the prescribing information for complete details or visit www.dechra-us.com.

To order, please contact your Dechra or distributor representative or call (866) 683-0660. 24-hour Technical Support available (866) 933-2472. Nonurgent Technical Support available via email support@dechra.com.

Dechra Veterinary Products US and the Dechra D logo are registered trademarks of Dechra Pharmaceuticals PLC.

Amoxicillin Trihydrate and Clavulanate Potassium Tablets ANADA 200-592, Approved by FDA CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. INDICATIONS: Amoxicillin Trihydrate and Clavulanate Potassium Tablets are indicated in the treatment of: Dogs: Skin and soft tissue infections such as wounds, abscesses, cellulitis, superficial/juvenile and deep pyoderma due to susceptible strains of the following organisms: β-lactamase-producing Staphylococcus aureus, non-β-lactamaseproducing Staphylococcus aureus, Staphylococcus spp., Streptococcus spp., and E. coli. Periodontal infections due to susceptible strains of both aerobic and anaerobic bacteria. Amoxicillin Trihydrate and Clavulanate Potassium Tablets have been shown to be clinically effective for treating cases of canine periodontal disease. Cats: Skin and soft tissue infections such as wounds, abscesses, and cellulitis/dermatitis due to susceptible strains of the following organisms: β-lactamase-producing Staphylococcus aureus, non-β-lactamase-producing Staphylococcus aureus, Staphylococcus spp., Streptococcus spp., E. coli, and Pasteurella spp. Urinary tract infections (cystitis) due to susceptible strains of E. coli. Therapy may be initiated with Amoxicillin Trihydrate and Clavulanate Potassium Tablets prior to obtaining results from bacteriological and susceptibility studies. A culture should be obtained prior to treatment to determine susceptibility of the organisms to Amoxicillin Trihydrate and Clavulanate Potassium Tablets. Following determination of susceptibility results and clinical response to medication, therapy may be reevaluated. CONTRAINDICATIONS: The use of this product is contraindicated in animals with a history of an allergic reaction to any of the penicillins or cephalosporins. WARNINGS: Safety of use in pregnant or breeding animals has not been determined. ADVERSE REACTIONS: Amoxicillin Trihydrate and Clavulanate Potassium Tablets contain a semisynthetic penicillin (amoxicillin) and have the potential for producing allergic reactions. If an allergic reaction occurs, administer epinephrine and/or steroids.

ADVERTISER INDEX

Advanced Veterinary Ultrasound Ultrasonography equipment . . . . . . 102

NAVC Bookstore . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 bookstore.navc.com

advancedveterinaryultrasound.com

Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

AAHA Accreditation program . . . . . . . . . . . . . . 91

navc.com

aaha.org

Institute . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 navc.com/institute

American College of Veterinary Internal Medicine ACVIM Forum . . . . . . . . . . . . . . . . . . . . . . . . 28

Live . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 navc.com/live

acvim.org

VIC Innovation Awards . . . . . . . . . . . . . 42

Antech Diagnostics Lab diagnostics . . . . . . . . . . . . . . . . . . . . . . . 19

vicawards.com

VMX 2018 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

antechdiagnostics.com

Bayer Seresto . . . . . . . . . . . . . . . . . . . . . . . . . 77, 79, 81 animalhealth.bayer.com

navc.com

National Veterinary Associates National Veterinary Associates . . . . 115 nvaonline.com

Synovi G4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 animalhealth.bayer.com

Nestlé Purina NeuroCare diet . . . . . . . . . . . . . . . . . . . . . . . 43 purina.com

Veraflox . . . . . . . . . . . . . . . . . . . . . . . . . . . 112, 113 animalhealth.bayer.com

Boehringer Ingelheim Vetmedin . . . . . . . . . . . . . . . . . . . . . . . . . . . 5, 12 boehringer-ingelheim.com

Dechra Amoxicillin/clavulanate . . . . . . . . . . . 9, 10 dechra-us.com

Zycortal . . . . . . . . . . . . . . . . . . . . . . . . . . . 61, 62 dechra-us.com

Elanco Ultra Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . 3 elanco.com

Fujifilm Digital x-ray solutions . . . . . . . . . . . . . . . 92 fujifilm.com

Henry Schein Vet Solutions Practice management solutions . . 87 poweringsuccessfulpractices.com

Masterfoods USA Royal Canin dermatology diets 14, 15 royalcanin.com

Merial Frontline Gold . . . . . . . . . . . . . . . . . . . . . . . 59 frontline.com

Heartgard . . . . . . . . . . . . . . 132, back cover

Nutramax Laboratories Proviable-Forte . . . . inside back cover nutramaxlabs.com

PNC Bank Financing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 pnc.com/en

Patterson Veterinary Schick33 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 schick33.com

Protege Biomedical Clotting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 protegebiomedical.com

Ultimed Inc iPet Pro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44 ulticare.com

VetFolio VetFolio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 vetfolio.com

Vetoquinol Lysine supplements . . . . . . . . . . . . . . . . . 85 vetoquinolusa.com

Vet’s First Choice Pharma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 vetsfirstchoice.com

Virbac Rebound Recuperation . . . . . . . . . . . . . . 31 virbacpets.com

heartgard.com

Sentinel Spectrum . . . . . . . . . . . . . . .52, 53

NexGard . . . . . . . . . . . . . . . . . 69, 70, insert nexgardfordogs.com

Manufactured for: Putney, Inc., a wholly owned subsidiary of Dechra Pharmaceuticals, PLC. Portland, ME 04101 USA 1-866-683-0660 Made in Austria.

Tresaderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 merial.com

virbacpets.com

Virox Technologies Disinfectants . . . . . . . . . . . . . . . . . . . . . . . . . 65 virox.com

Midmark Midmark products . . . . . . . . . . . . . . . . . . . 89

Zoetis Cytopoint . . . . . . . . . inside front cover, 1

midmarkanimalhealth.com

zoetis.com

Simparica . . . . . . . . . . . . . . . . . . . . . . . . 49, 50 simparica.com

TABLE OF CONTENTS 10

AD INDEX

Thomas M. Bohn, CAE NAVC Chief Executive Officer NAVC PERSPECTIVES

NAVC PERSPECTIVES

There’s No Place Like Home This year, the NAVC Conference welcomed tens of thousands of veterinary professionals from over 80 countries to its new home at the Orange County Convention Center in Orlando, Florida. And that was pretty exciting for all of us here at the NAVC. For the first time ever, all the sessions were in one centralized location, from Handson Laboratories to Masterclasses to much, much more. We had one enormous Exhibit Hall, and major hotels and restaurants within walking distance—a perfect setting for networking, learning, and getting that inspiration that is part of the unique NAVC Conference experience.

and a large and diverse exhibitor hall— everything you’ve come to expect from us! With this new name and mission, the NAVC is making sure the conference continues to be a priceless investment for all its attendees.

NEW NAME, SAME FIRSTCLASS EXPERIENCE

NAVC Institute (Orlando, Florida; May 21-26, 2017)

We wouldn’t be the NAVC you’ve grown to value if we weren’t constantly improving our conference experience and looking for ways to serve the industry better. With that in mind, we are proud to introduce next year’s NAVC Conference as the 2018 Veterinary Meeting & Expo. VMX will offer world-class continuing education, top-tier entertainment, unparalleled networking opportunities, innovative product launches,

CONTINUING EDUCATION ALL YEAR LONG But of course, that’s not all. We’ve got great events throughout the year to give you that extra infusion of creativity, training, and vision. Here’s just some of what’s ahead in 2017 (learn more at navc.com/ce-events):

This hands-on learning experience brings you face to face with leaders in the veterinary practice. As always, the Institute will let you focus your full attention on mastering valuable skills while enjoying one-on-one interaction with a board-certified course leader. Veterinary Innovation Summit (College Station, Texas; April 28-30, 2017) This is the perfect CE opportunity for those who consider themselves innovative thinkers and disruptors. What does that mean? Well, it’s about connecting with other people who also want to be change leaders in the industry. Organizers of the conference promise this will be one of the most unique veterinary conferences ever offered. NAVC Discovery: Buffalo (Buffalo, New York; July 29-August 3, 2017) Much like the annual NAVC Institute, NAVC Discovery: Buffalo is a hands-on veterinary event

Conference attendees look forward to next year’s conference: the 2018 Veterinary Meeting & Expo.

NAVC PERSPECTIVES continued on page 102

MARCH/APRIL 2017

■

TVPJOURNAL.COM

090340591/0 NADA 141-273, Approved by FDA

Vetmedin® (pimobendan) Chewable Tablets

Cardiac drug for oral use in dogs only Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian. Description: Vetmedin (pimobendan) is supplied as oblong half-scored chewable tablets containing 1.25, 2.5, 5 or 10 mg pimobendan per tablet. Pimobendan, a benzimidazole-pyridazinone derivative, is a non-sympathomimetic, non-glycoside inotropic drug with vasodilatative properties. Pimobendan exerts a stimulatory myocardial effect by a dual mechanism of action consisting of an increase in calcium sensitivity of cardiac myofilaments and inhibition of phosphodiesterase (Type III). Pimobendan exhibits vasodilating activity by inhibiting phosphodiesterase III activity. The chemical name of pimobendan is 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole5-yl]-5-methyl-3(2H)-pyridazinone. The structural formula of pimobendan is:

Indications: Vetmedin (pimobendan) is indicated for the management of the signs of mild, moderate, or severe (modified NYHA Class IIa, IIIb, or IVc) congestive heart failure in dogs due to atrioventricular valvular insufficiency (AVVI) or dilated cardiomyopathy (DCM). Vetmedin is indicated for use with concurrent therapy for congestive heart failure (e.g., furosemide, etc.) as appropriate on a case-by-case basis. a

A dog with modified New York Heart Association (NYHA) Class II heart failure has fatigue, shortness of breath, coughing, etc. apparent when ordinary exercise is exceeded.

A dog with modified NYHA Class III heart failure is comfortable at rest, but exercise capacity is minimal.

A dog with modified NYHA Class IV heart failure has no capacity for exercise and disabling clinical signs are present even at rest.

Dosage and Administration: Vetmedin should be administered orally at a total daily dose of 0.23 mg/lb (0.5 mg/kg) body weight, using a suitable combination of whole or half tablets. The total daily dose should be divided into 2 portions that are not necessarily equal, and the portions should be administered approximately 12 hours apart (i.e., morning and evening). The tablets are scored and the calculated dosage should be provided to the nearest half tablet increment. Contraindications: Vetmedin should not be given in cases of hypertrophic cardiomyopathy, aortic stenosis, or any other clinical condition where an augmentation of cardiac output is inappropriate for functional or anatomical reasons. Warnings: Only for use in dogs with clinical evidence of heart failure. At 3 and 5 times the recommended dosage, administered over a 6-month period of time, pimobendan caused an exaggerated hemodynamic response in the normal dog heart, which was associated with cardiac pathology (See Animal Safety). Human Warnings: Not for use in humans. Keep this and all medications out of reach of children. Consult a physician in case of accidental ingestion by humans. Precautions: The safety of Vetmedin has not been established in dogs with asymptomatic heart disease or in heart failure caused by etiologies other than AVVI or DCM. The safe use of Vetmedin has not been evaluated in dogs younger than 6 months of age, dogs with congenital heart defects, dogs with diabetes mellitus or other serious metabolic diseases, dogs used for breeding, or pregnant or lactating bitches. Adverse Reactions: Clinical findings/adverse reactions were recorded in a 56-day field study of dogs with congestive heart failure (CHF) due to AVVI (256 dogs) or DCM (99 dogs). Dogs were treated with either Vetmedin (175 dogs) or the active control enalapril maleate (180 dogs). Dogs in both treatment groups received additional background cardiac therapy (See Effectiveness for details and the difference in digoxin administration between treatment groups). The Vetmedin group had the following prevalence (percent of dogs with at least one occurrence) of common adverse reactions/new clinical findings (not present in a dog prior to beginning study treatments): poor appetite (38%), lethargy (33%), diarrhea (30%), dyspnea (29%), azotemia (14%), weakness and ataxia (13%), pleural effusion (10%), syncope (9%), cough

of pimobendan and active metabolite and the maximum physiologic response (peak LV dP/dtmax). Blood levels of pimobendan and active metabolite began to drop before maximum contractility was seen. Repeated oral administration of pimobendan did not result in evidence of tachyphylaxis (decreased positive inotropic effect) or Adverse reactions/new clinical findings were seen in drug accumulation (increased positive inotropic effect). both treatment groups and were potentially related to CHF, the therapy of CHF, or both. The following adverse Laboratory studies indicate that the positive inotropic effect of pimobendan may be attenuated by the reactions/new clinical findings are listed according to concurrent use of a β-adrenergic blocker or a calcium body system and are not in order of prevalence: CHF channel blocker. death, sudden death, chordae tendineae rupture, left atrial tear, arrhythmias overall, tachycardia, syncope, Effectiveness: In a double-masked, multi-site, 56-day weak pulses, irregular pulses, increased pulmonary field study, 355 dogs with modified NYHA Class II, III, or edema, dyspnea, increased respiratory rate, coughing, IV CHF due to AVVI or DCM were randomly assigned gagging, pleural effusion, ascites, hepatic congestion, to either the active control (enalapril maleate) or the decreased appetite, vomiting, diarrhea, melena, weight Vetmedin (pimobendan) treatment group. Of the 355 loss, lethargy, depression, weakness, collapse, shaking, dogs, 52% were male and 48% were female; 72% were trembling, ataxia, seizures, restlessness, agitation, diagnosed with AVVI and 28% were diagnosed with pruritus, increased water consumption, increased DCM; 34% had Class II, 47% had Class III, and 19% urination, urinary accidents, azotemia, dehydration, had Class IV CHF. Dogs ranged in age and weight abnormal serum electrolyte, protein, and glucose from 1 to 17 years and 3.3 to 191 lb, respectively. The values, mild increases in serum hepatic enzyme levels, most common breeds were mixed breed, Doberman and mildly decreased platelet counts. Pinscher, Cocker Spaniel, Miniature/Toy Poodle, See Table 1 for mortality due to CHF (including Maltese, Chihuahua, Miniature Schnauzer, Dachshund, euthanasia, natural death, and sudden death) and for and Cavalier King Charles Spaniel. The 180 dogs (130 the development of new arrhythmias (not present in a AVVI, 50 DCM) in the active control group received dog prior to beginning study treatments) by treatment enalapril maleate (0.5 mg/kg once or twice daily), and group and type of heart disease (AVVI or DCM) in the all but 2 received furosemide. Per protocol, all dogs 56-day field study. with DCM in the active control group received digoxin. The 175 dogs (126 AVVI, 49 DCM) in the Vetmedin Table 1: CHF Death and New Arrhythmias group received pimobendan (0.5 mg/kg/day divided in the 56-Day Field Study into 2 portions that were not necessarily equal, and the ® Vetmedin Active Control portions were administered approximately 12 hours Group Group apart), and all but 4 received furosemide. Digoxin was Dogs that 14.3% 14.4% optional for treating supraventricular tachyarrhythmia died n = 175 n = 180 in either treatment group, as was the addition of a due to CHF β-adrenergic blocker if digoxin was ineffective in 9 of 126 dogs 16 of 130 dogs controlling heart rate. After initial treatment at the clinic with AVVI with AVVI on Day 1, dog owners were to administer the assigned 16 of 49 dogs 10 of 50 dogs product and concurrent medications for up to 56±4 days. with DCM with DCM The determination of effectiveness (treatment success) Dogs that 39.4% 45.0% for each case was based on improvement in at developed n = 175 n = 180 least 2 of the 3 following primary variables: modified new a 45 of 126 dogs 59 of 130 dogs NYHA classification, pulmonary edema score by a arrhythmias with AVVI with AVVI masked veterinary radiologist, and the investigator’s overall clinical effectiveness score (based on physical 24 of 49 dogs 22 of 50 dogs examination, radiography, electrocardiography, and with DCM with DCM clinical pathology). Attitude, pleural effusion, coughing, a New arrhythmias included supraventricular premature activity level, furosemide dosage change, cardiac beats and tachycardia, atrial fibrillation, atrioventricular size, body weight, survival, and owner observations were secondary evaluations contributing information block, sinus bradycardia, ventricular premature beats supportive to product effectiveness and safety. and tachycardia, and bundle branch block Based on protocol compliance and individual case Following the 56-day masked field study, 137 dogs integrity, 265 cases (134 Vetmedin, 131 active control) in the Vetmedin group were allowed to continue on were evaluated for treatment success on Day 29. See Vetmedin in an open-label extended-use study without Table 2 for effectiveness results. restrictions on concurrent therapy. The adverse reactions/new clinical findings in the extended-use Table 2: Effectiveness Results study were consistent with those reported in the 56-day for the 56-Day Field Study study, with the following exception: One dog in the Vetmedin® Active Control extended-use study developed acute cholestatic liver Group Group failure after 140 days on Vetmedin and furosemide. Treatment 80.7% 76.3% In foreign post-approval drug experience reporting, the Success on n=134 n=131 following additional suspected adverse reactions were Day 29 88 of 101 dogs 77 of 100 dogs reported in dogs treated with a capsule formulation with AVVI with AVVI of pimobendan: hemorrhage, petechia, anemia, hyperactivity, excited behavior, erythema, rash, 20 of 33 dogs 23 of 31 dogs drooling, constipation, and diabetes mellitus. with DCM with DCM To report suspected adverse reactions, to obtain a Treatment 71.1% 67.2% Material Safety Data Sheet, or for technical assistance Success on n=113 n=110 call 1-866-638-2226. Day 56 66 of 85 dogs 56 of 85 dogs Clinical Pharmacology: Pimobendan is oxidatively with AVVI with AVVI demethylated to a pharmacologically active metabolite 13 of 28 dogs 17 of 25 dogs which is then conjugated with sulfate or glucuronic with DCM with DCM acid and excreted mainly via feces. The mean extent of protein binding of pimobendan and the active No increase metabolite in dog plasma is >90%. Following a single in furosemide 78.3% 68.6% oral administration of 0.25 mg/kg Vetmedin tablets dose between n=130 n=126 the maximal mean (± 1 SD) plasma concentrations Day 1 and (Cmax) of pimobendan and the active metabolite were Day 29 3.09 (0.76) ng/ml and 3.66 (1.21) ng/ml, respectively. Individual dog Cmax values for pimobendan and the At the end of the 56-day study, dogs in the Vetmedin active metabolite were observed 1 to 4 hours postgroup were enrolled in an unmasked field study to dose (mean: 2 and 3 hours, respectively). The total monitor safety under extended use, without restrictions body clearance of pimobendan was approximately on concurrent medications. 90 mL/min/kg, and the terminal elimination half-lives Vetmedin was used safely in dogs concurrently of pimobendan and the active metabolite were receiving furosemide, digoxin, enalapril, atenolol, approximately 0.5 hours and 2 hours, respectively. spironolactone, nitroglycerin, hydralazine, diltiazem, Plasma levels of pimobendan and active metabolite antiparasitic products (including heartworm were below quantifiable levels by 4 and 8 hours after prevention), antibiotics (metronidazole, cephalexin, oral administration, respectively. The steady-state amoxicillin-clavulanate, fluoroquinolones), topical volume of distribution of pimobendan is 2.6 L/kg ophthalmic and otic products, famotidine, theophylline, indicating that the drug is readily distributed into levothyroxine sodium, diphenhydramine, hydrocodone, tissues. Food decreased the bioavailability of an aqueous solution of pimobendan, but the effect of food metoclopramide, and butorphanol, and in dogs on on the absorption of pimobendan from Vetmedin tablets sodium-restricted diets. is unknown. Palatability: In a laboratory study, the palatability of Vetmedin was evaluated in 20 adult female Beagle In normal dogs instrumented with left ventricular (LV) dogs offered doses twice daily for 14 days. Ninety pressure transducers, pimobendan increased LV dP/ percent (18 of 20 dogs) voluntarily consumed more dtmax (a measure of contractility of the heart) in a than 70% of the 28 tablets offered. Including two dogs dose dependent manner between 0.1 and 0.5 mg/ that consumed only 4 and 7% of the tablets offered, the kg orally. The effect was still present 8 hours after average voluntary consumption was 84.2%. dosing. There was a delay between peak blood levels

(7%), sudden death (6%), ascites (6%), and heart murmur (3%). Prevalence was similar in the active control group. The prevalence of renal failure was higher in the active control group (4%) compared to the Vetmedin group (1%).

Animal Safety: In a laboratory study, Vetmedin chewable tablets were administered to 6 healthy Beagles per treatment group at 0 (control), 1, 3, and 5 times the recommended dosage for 6 months. See Table 3 for cardiac pathology results. The cardiac pathology/histopathology noted in the 3X and 5X dose groups is typical of positive inotropic and vasodilator drug toxicity in normal dog hearts, and is associated with exaggerated hemodynamic responses to these drugs. None of the dogs developed signs of heart failure and there was no mortality. Table 3: Incidence of Cardiac Pathology/ Histopathology in the Six-month Safety Study Severe left ventricular hypertrophy with multifocal subendocardial ischemic lesions

One 3X and two 5X dogsa

Moderate to marked myxomatous thickening of the mitral valves

Three 5X dogs

Myxomatous thickening of the chordae tendineae

One 3X and two 5X dogs

Endocardial thickening of the left ventricular outflow tract

One 1X, two 3X, and two 5X dogs

Left atrial endocardial thickening (jet lesions) in 2 of the dogs that developed murmurs of mitral valve insufficiency

One 3X and one 5X dog

Granulomatous inflammatory lesion in the right atrial myocardium

One 3X dog

Most of the gross and histopathologic findings occurred in these three dogs

Murmurs of mitral valve insufficiency were detected in one 3X (Day 65) and two 5X dogs (Days 135 and 163). These murmurs (grades II-III of VI) were not associated with clinical signs. Indirect blood pressure was unaffected by Vetmedin at the label dose (1X). Mean diastolic blood pressure was decreased in the 3X group (74 mmHg) compared to the control group (82 mmHg). Mean systolic blood pressure was decreased in the 5X group (117 mmHg) compared to the control group (124 mmHg). None of the dogs had clinical signs of hypotension. On 24-hour Holter monitoring, mean heart rate was increased in the 5X group (101 beats/min) compared to the control group (94 beats/min). Not counting escape beats, the 3X and 5X groups had slightly higher numbers of isolated ventricular ectopic complexes (VEs). The maximum number of non-escape VEs recorded either at baseline or in a control group dog was 4 VEs/24 hours. At either Week 4 or Week 20, three 3X group dogs had maximums of 33, 13, and 10 VEs/24 hours, and two 5X group dogs had maximums of 22 and 9 VEs/24 hours. One 1X group dog with no VEs at baseline had 6 VEs/24 hours at Week 4 and again at Week 20. Second-degree atrioventricular heart block was recorded in one 3X group dog at Weeks 4 and 20, and in one dog from each of the 1X and 5X groups at Week 20. None of the dogs had clinical signs associated with these electrocardiogram changes. Treatment was associated with small differences in mean platelet counts (decreased in the 3X and 1X groups), potassium (increased in the 5X group), glucose (decreased in the 1X and 3X groups), and maximum blood glucose in glucose curves (increased in the 5X group). All individual values for these variables were within the normal range. Three 1X and one 5X group dogs had mild elevations of alkaline phosphatase (less than two times normal). Loose stools and vomiting were infrequent and self-limiting. Storage Information: Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (between 59° and 86°F). How Supplied: Vetmedin® (pimobendan) Chewable Tablets: Available as 1.25, 2.5, 5 and 10 mg oblong half-scored chewable tablets - 50 tablets per bottle. NDC 0010-4480-01-1.25 mg - 50 tablets NDC 0010-4481-01-2.5 mg - 50 tablets NDC 0010-4482-01-5 mg - 50 tablets NDC 0010-4479-01-10 mg - 50 tablets Manufactured by: Boehringer Ingelheim Promeco S.A. de C.V. Mexico City, Mexico Manufactured for: Boehringer Ingelheim Vetmedica, Inc. St. Joseph, MO 64506 U.S.A. Vetmedin® is a registered trademark of Boehringer Ingelheim Vetmedica GmbH licensed to Boehringer Ingelheim Vetmedica, Inc. Copyright © 2013 Boehringer Ingelheim Vetmedica, Inc. or an affiliated company. All Rights Reserved. 448005-00 Revised 06/2013

Simon R. Platt , BVM&S, MRCVS, DACVIM (Neurology) & DECVN University of Georgia

EDITOR’S NOTE

Grief: The Secret Among Us?

“ Though nothing can bring back the hour of splendour in the grass, of glory in the flower, we will grieve not, rather find strength in what remains behind.”

William Wordsworth,

I ntimations of Immortality from Recollections of Early Childhood

As veterinarians, we deal with more “client”related grief than many other professionals. The death of a pet means the loss of a source of love, of a living being to care for, and of contact with a component of our natural world. While the grief suffered by pet owners after a pet dies is recognized to be the same as that experienced after the death of a person, the world rarely affords the same empathy to this situation as it does to the loss of a human family member. It definitely doesn’t afford much empathy to the veterinarian who has to deal with the loss of a (perhaps well-known) patient and with its owner’s grief. We rarely feel capable or comfortable with this all-too-frequent occurrence in our lives, but we survive it by using the pieces of humanity we possess and the collective experiences we have learned over the length of our careers. The stages of grief and mourning are universal and are experienced by people from all walks of life, across many cultures. Mourning is a response to an individual’s own terminal illness, the loss of a close relationship, or to the death of a valued being, whether human or animal.

The 5 stages of grief that people experience were first proposed by Elisabeth Kübler-Ross in her 1969 book On Death and Dying. Denial, anger, bargaining, depression, and acceptance can all be experienced for different lengths of time, and everyone works through each step and expresses each stage with different levels of intensity. Although these stages do not necessarily occur in any specific order, as veterinarians, we may have the most experience witnessing the denial and anger stages, and sometimes these may be focused toward us, despite our obvious and best intentions. What should our role be? How do we deal with the emotional and mental stress that we take on during these times? With respect to the latter, do we call it “compassion fatigue” or simple emotional and mental fatigue? Whatever we call it, whether we feel fatigued or not, such stress leaves its scars. We carry it with us. It affects our lives and the lives of those around us. Some large practices employ grief counselors to help owners deal with their loss and emotions. Many other practices have grief counseling brochures to assist owners in finding a source of support at their time of need. As individuals, we can at least suggest one of a plethora of pet loss support hotlines and groups. However, the acute and variable display of grief-associated emotions often leaves us as the frontline counselors, for which many of us are inadequately trained but which we take on as a recognized part of our job. So, in answer to the question, “What should our role be?”: It is what we choose it to be. Many of us choose to be on the front line, guiding owners to self-help options as needed. The answer to the second question—“How do

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we deal with it?”—needs more focus from the profession as a whole. Not many practices around the world employ counselors for the mental health of veterinary staff faced with clients’ grief, with which we may closely identify. It would seem that we are on our own in trying to understand how we as individuals best deal with this challenge and how we can keep our emotional and mental strength at a level that enables a healthy life and a successful career.

Our canine

Thankfully, the veterinary profession is recognizing and accepting that we need assistance in dealing with the mental health stresses that we all too often endure. However, we should not have to wait until we need help! Our ability to handle the grief experienced by our clients, whether “successful” or not, can contribute to our need for help, so being prepared may be the best medicine, and education is the best preparation. As an example of how we can educate ourselves, the American Institute of Health Care Professionals offers an online pet loss grief recovery certification course.

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As veterinarians, we deal with a multitude of challenges that affect our mental and emotional wellbeing. Confronted together, they may feel overwhelming; however, addressed on an individual basis, they may be more manageable. Understanding how we should deal with the grief in our job is something well worth focusing on. We practice that prevention is better than cure for our patients. It is high time that we admitted we should follow our own advice and that dealing with daily grief is our worst-kept secret.

Grief Counseling Resources For clients •R ainbow Bridge: rainbowsbridge.com/Grief_Support_ Center/Grief_Support_Home.htm •A ssociation for Pet Loss and Bereavement: aplb.org/ support/support_groups/ For veterinary professionals •A VMA Guidelines for Pet Loss Support Services: avma. org/KB/Policies/Pages/AVMA-Guidelines-for-Pet-LossSupport-Services.aspx •A merican Institute of Health Care Professionals Pet Loss Grief Recovery Certification: aihcp.net/pet-loss-griefrecovery-certification/ © ROYAL CANIN® SAS 2016. All Rights Reserved.

Derm Canine Print 2 x 9.5_final.indd 1

1/30/17 11:15 AM

EDITOR’S NOTE

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NEW

TODAY’S VETERINARY NEWS

New Website for Cat Caregivers The American Association of Feline Practitioners (AAFP) has launched “The Cat Community” at catfriendly.com. Powered by feline veterinarians, catfriendly.com provides cat caregivers with reliable and valuable educational information. Cat caregivers will be able to learn about their cat’s innate behaviors, the importance of routine veterinary care, and how to take great care of their cat, as well as answer many of their most pressing questions. Veterinary professionals can use the website as a client resource. The site also features a “Find a Veterinarian or Practice” search database so cat caregivers can locate an AAFP member veterinarian or Cat Friendly Practice in their area. ■ Visit catfriendly.com to learn more!

NEW ANIMATION FOR PLATELET-RICH PLASMA THERAPY Companion Animal Health has pioneered a first-in-class medical animation overviewing platelet biology and the effects of platelet-rich plasma (PRP). This animation provides the viewer with a biologic background into this groundbreaking therapy, following the steps of PRP processing to injection, resulting in tissue healing and repair. Educational for both veterinary professionals and pet owners alike, this animation brings to life this clinically effective therapy in a simplified manner. ■ View the animation by visiting www.LiteCureInfo.com/HowDoesPRPWork.

TODAY’S VETERINARY NEWS

helps you make the most of your practice’s cash flow.

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TODAY’S VETERINARY NEWS

MAKER OF HEARTGARD PLUS TO DONATE $100K TO VETERAN-FOCUSED NONPROFIT Merial, the maker of HEARTGARD Plus, announced a new partnership with Warrior Canine Connection, a Washington DC-based nonprofit that offers assistance to service members and veterans affected by the invisible wounds of war by providing them with highly skilled service dogs. As part of the partnership, Merial will donate $100,000 to support Warrior Canine Connection’s work and the rehabilitating power of the human-animal bond. In doing so, Merial hopes to enhance the health of service members and veterans and raise awareness of canine heartworm disease prevention. ■ Learn more at warriorcanineconnection.org and heartgard.com.

, Lansford st Justin Speciali y (Ret) US Arm

Sergeant Matt Moores, US Marine Corps (Ret)

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NEW EDITOR FOR THE MERCK VETERINARY MANUAL

NEW ADVISORY BOARD TO ADVANCE THERAPEUTIC NUTRITION

Merck and Co, Inc has announced that Scott Line, DVM, PhD, DACVB, has been named Editor-in-Chief of The Merck Veterinary Manual, the company’s renowned animal health reference. Dr. Line graduated summa cum laude from Ohio State University, where he also received his doctor of veterinary medicine degree. He later earned a PhD in animal behavior from the University of California at Davis, where he also served as a resident at the School of Veterinary Medicine. The Merck Veterinary Manual has been trusted by veterinarians, veterinary students, veterinary technicians, and other animal health professionals since 1955. The 11th edition was published in the summer of 2016 and contains contributions from nearly 400 veterinary experts.

Blue Buffalo has announced the formation of an ongoing Veterinary Advisory Board to provide input on natural, therapeutic nutritional advances that will be most valued by veterinarians and their clients. The diverse group of independent advisors will also focus on Blue Buffalo–sponsored scientific research and evidence-based treatments. This ongoing collaborative effort will provide all veterinary clinics with important information and solutions to enable them to better serve and recommend researchbacked, natural dietary solutions for their patients.

■ I t can be ordered at merckbooks.com, by calling 1-877-762-2974, or at navc.com/bookstore.

Sergea

TODAY’S VETERINARY NEWS

■T o learn more, visit bluebuffalo.com/ about-us/whats-new-at-blue.

TODAY’S VETERINARY NEWS continued on page 28

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URETHRAL INCOMPETENCE IN DOGS

CONTINUING EDUCATION

CANINE URINARY INCONTINENCE

Urethral Incompetence in Dogs: Updates in Management Julie K. Byron, DVM, MS, DACVIM The Ohio State University College of Veterinary Medicine

Urethral incompetence is the most common reason for urinary incontinence in the dog. Management of these patients can start out as being relatively straightforward; however, many dogs need adjustments in their therapy as they age or develop additional health concerns. This article reviews the medical and surgical options available for treatment of urethral incompetence and provides guidelines to choosing the best one for each patient, as well as comments on prevention for potentially at-risk dogs.

MEDICAL THERAPY Medical therapy is considered the first line of management in dogs with acquired urethral incompetence (UI). Often it is initiated on an empirical basis, with minimal pretreatment diagnostics other than a urinalysis and urine culture. In spayed female dogs, this is acceptable; however, in intact females and in males, further

evaluation for other urinary tract disorders, particularly urethral functional obstruction and overflow incontinence, is warranted. Medical therapy is most commonly aimed at increasing urethral tone by stimulating α-receptors in the smooth muscle of the urethra with α-agonists and/or increasing the number and sensitivity of those receptors with estrogen compounds. Estrogen also appears to have a trophic effect on the periurethral tissues and vasculature and thus may reduce incontinence through improved urethral support. In addition, there is ongoing investigation into other hormones in the pituitary-gonadal axis and their role in urethral incompetence.

CE TEST To view the CE test for this article, please visit tvpjournal.com.

URETHRAL INCOMPETENCE is most common in dogs who are spayed or neutered; however, the exact mechanism and relationship to estrogen and testosterone decline is unclear.

shutterstock.com/S Curtis

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α-Agonist Therapy α-Receptors, which are part of the sympathetic nervous system, are mediators of smooth muscle contraction and relaxation in a variety of tissues. Stimulation of α1A receptors in the smooth muscle of the urethra and bladder neck leads to increased urethral closure pressures and is an important part of resting urethral tone. α1-Agonists are likely the most commonly used UI therapy in veterinary medicine. α-Agonists can be used in dogs and cats and in both sexes. The most serious potential adverse effect is hypertension, because of the lack of specificity of the agonists for the lower urinary tract and stimulation of vascular smooth muscle. Other adverse effects, such as behavioral changes and decreased appetite, are related to sympathetic stimulation.

poorer than in female dogs. This is possibly caused by misdiagnosis of dogs with functional urethral obstruction and overflow incontinence. PPA has also been used safely in cats with UI, although there are little data available regarding its efficacy. Hypertension, or a predisposition to hypertension caused by concurrent disease, is a major contraindication to using PPA. In otherwise healthy dogs with normal blood pressure, PPA rarely induced hypertension at recommended doses.3,4 However, in patients with conditions such as chronic kidney disease, hyperadrenocorticism, and protein-losing nephropathy, it should be used with extreme caution and blood pressure should be regularly monitored. A good general guideline is to perform an indirect systolic blood pressure on any patient before treatment with PPA and repeat the evaluation after 1 to 2 weeks of therapy. Milder adverse effects associated with PPA include restlessness, aggression, changes in sleeping patterns, and gastrointestinal signs. These are also usually alleviated by a reduction in dose or frequency.1,5

Phenylpropanolamine (PPA) (Proin, prnpharmacal.com) is the most widely used α-agonist for the treatment of UI. This FDA-approved drug is commercially available in doses designed for use in dogs. The dose and frequency needed for each animal tend to vary widely and may need to be increased over time to maintain continence (Table 1).

Estrogen Therapy

Clinical response to PPA administration ranges from 75% to 90%.1,2 Male dogs with UI can be treated with PPA; however, the response (<50%) is

Estrogen therapy has been used to treat incontinence for decades. Estrogen plays an important role in the strength and robustness

TABLE 1 Dosages of Drugs for Management of Urethral Incompetence DRUG CLASSIFICATION

DRUG

DOSAGE

α-Agonist

Phenylpropanolamine

0.5–1.5 mg/kg PO q8–12h

Estriol

2 mg/dog PO q24h for 14 days, then 1 mg/dog PO q24h for 14 days, then 0.5 mg/dog PO q24h, then maintenance at the lowest effective dose

Diethylstilbestrol

1 mg/dog PO q24h for 7 days, then q 5–7 days, then adjusted for efficacy

Conjugated estrogen

0.02 mg/kg PO q24h for 5–7 days, then q 2–4 days, adjusting as needed

GnRH analog

Depot deslorelin acetate

5–10 mg/dog SC q 6 months*

Testosterone

Testosterone cypionate

2.2 mg/kg IM monthly

Estrogen compound

*The dose listed is extrapolated from human doses; the dosing interval varies widely, with the average based on limited studies. The author recommends that the dosing interval be based on recurrence of clinical signs in the individual dog.

URETHRAL INCOMPETENCE IN DOGS

CONTINUING EDUCATION

of pelvic and periurethral tissues. It enhances glandular function, impacts collagen strength, and increases the number and sensitivity of Îą-receptors in the smooth muscle of the urethra. There is strong evidence that estrogen increases the baseline resting urethral pressure in animal models of incontinence.6 These compounds are usually well tolerated and are a good choice for female dogs with concurrent diseases that predispose them to hypertension or that are intolerant of Îą-agonist treatment. Estrogens should not be used in male dogs because of the potential for prostatic squamous metaplasia.7 The use of estrogens in cats with UI has not been reported and is controversial. Although there has been speculation on the role of estrogens in the development of feline mammary neoplasia, a direct link has yet to be proven. Some practitioners avoid the use of estrogen compounds because of the potential for irreversible myelosuppression seen in dogs treated with estrogen compounds for mismating or to induce estrus.8,9 While this is a potential toxicosis, the doses associated with bone marrow suppression are generally at least 10 times higher than those recommended for management of UI. The need for monitoring for signs of bone marrow suppression with a complete blood count is controversial, and agreed-upon standard of care recommendations cannot be given. However, caution should be taken when using these compounds in patients with underlying myelosuppressive disease or at high doses. Estriol (Incurin, merck-animal-health-usa.com) is the only commercially available FDA-approved estrogen for the treatment of UI in the United States (Table 1). Female dogs appear to have similar response rates to estriol and DES (89% and 87%, respectively).9,10 Adverse effects with its use include mammary and vulvar swelling and attractiveness to male dogs. These side effects are generally mild and resolve with appropriate dose reduction. Diethylstilbestrol (DES) is a synthetic, nonsteroidal estrogen first synthesized in 1938. It was widely used in the United States and

worldwide to reduce pregnancy complications and treat a variety of conditions in women until 1971; it was found to contribute to an increased risk of neoplasia and birth defects in the children of expectant mothers who took the drug. Since that time, DES has not been available commercially and is only available to the veterinary community through compounding pharmacies. DES has been used to treat UI in dogs for more than 40 years, although there are few studies evaluating its efficacy.9 Adverse effects are similar to those seen with other estrogens, such as mammary and vulvar swelling and attractiveness to males. As with estriol, these are usually doserelated and subside with dose reduction. One advantage of using DES to treat UI in dogs is the convenience of treating a patient on a weekly basis rather than daily (Table 1). In addition, treatment frequency can be adjusted (eg, every 5 days rather than every 7) to accommodate the declining response to treatment in some patients without having to increase the capsule size or medicate multiple times a day. Conjugated estrogens (Premarin, pfizer.com) naturally derived from the urine of pregnant mares have been used to treat a variety of postmenopausal symptoms in women. There are anecdotal reports of the successful use of conjugated estrogens in spayed female dogs with UI (Table 1); however, no studies have been published. It is likely that the efficacy and adverse effect profile are similar to those of DES.

Gonadotropin-Releasing Hormone (GnRH) Analogs In the spayed female dog, the removal of the negative feedback effect of estrogen leads to increases in follicle stimulating hormone (FSH) and luteinizing hormone (LH). It has been hypothesized that the increase in these gonadotropins has either a direct negative impact on the urethral closure pressure or results in decreased bladder function.11,12 The use of depot GnRH analogs, such as depot deslorelin acetate (Table 1), which ultimately MARCH/APRIL 2017

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decrease LH and FSH, has been investigated in incontinent spayed females and was found to be 54% effective when used alone and 92% effective when combined with PPA.13 Ongoing investigation into the use of gonadotropin immunization and other related therapies is promising, although FSH and LH suppression has yet to become a widespread treatment for UI. In addition, some preparations are very costly and others are not available in North America.

Testosterone Cypionate Testosterone cypionate has had some anecdotal use in males with UI and may provide some improvement (Table 1). It is unclear whether this is a direct effect on the urethral musculature, its support structures, or increased prostatic urethral resistance. No studies have been performed to assess its efficacy in male dogs with UI. Adverse effects associated with testosterone supplementation include behavior changes and prostatic hyperplasia.

FAILURE OF MEDICAL THERAPY Frequently both an estrogen and PPA are used in the same patient for severe or refractory incontinence. Evidence supporting a synergistic increase in efficacy is controversial; however, anecdotal reports of greater improvement than on a single medication regimen exist.14,15

Dogs that do not respond to appropriate medical therapy should be evaluated for other lower urinary tract disease via imaging, including abdominal ultrasonography and/or contrast radiography. Cystoscopy is routinely performed in patients with urinary incontinence to rule out anatomic abnormalities that may be contributing to clinical signs. Urodynamic evaluation can be performed to rule out overactive bladder and confirm the diagnosis of UI. Male dogs should be evaluated for urine retention and functional urethral obstruction. For patients with UI that fail medical therapy, or for which medical therapy is not an option, several interventional and surgical options exist. When evaluating the published success of these procedures, it is important to note that they have primarily been evaluated in patients that are not responding to medical therapy and thus may have a more severe form of urethral sphincter mechanism incompetence (USMI). No studies have evaluated them as first-line treatment options.

INTERVENTIONAL PROCEDURES Urethral Bulking Injectable urethral bulking agents, particularly bovine crosslinked collagen, have been used to increase resting urethral pressure in dogs

FIGURE 1. Urethral bulking agent. Cystoscopic view showing the placement of the injection needle under the urethral mucosa (A), and the final narrowed lumen after injection of bovine crosslinked collagen (B). Images courtesy of Julie K. Byron, DVM, MS, DACVIM, The Ohio State University.

URETHRAL INCOMPETENCE IN DOGS

CONTINUING EDUCATION

with UI. Although many materials have been investigated, the theory behind all injectable bulking agents is to increase the stretch in the sphincter muscle fibers, leading to an increased resting closure pressure in the urethra. In addition, the implant may narrow the diameter of the urethral lumen, allowing the urethral sphincter to close more effectively. The material is injected submucosally into the proximal urethra via cystoscopy (Figure 1). Based on two long-term reviews, postprocedure continence in female dogs with UI was 66% to 68%; of those who are not continent, 46% to 60% achieved continence with the addition of medical therapy.16,17 The largest drawback of this procedure is the variability in duration of effect. Median duration of continence without additional medical therapy ranged from 8 months to 2 years.

Continence was maintained for up to 2 years in 4 of 4 dogs.18 In a recent review, 27 of 27 dogs had significantly improved continence scores after placement of the sphincter, with only 2 dogs having complications involving partial urethral obstruction.19 Surgical placement of an artificial urethral sphincter appears to have good success in male dogs that fail medical therapy.

SURGICAL THERAPY Surgical management of UI is chosen for dogs intolerant of medical treatment or, most often, with progressive and refractory incontinence. Surgical therapy of urinary incontinence has traditionally focused on increasing the transmission of intra-abdominal pressure to the proximal urethra or improving the stability and pressure within the urethra.

Artificial Urethral Sphincter Placement A newer procedure for canine urinary incontinence is gaining in popularity and availability. The surgical placement of an artificial adjustable hydraulic urethral sphincter (Figure 2) around the urethra has been studied in female dogs and anecdotally used in males. The device allows the dog to urinate normally while maintaining continence. A small port is connected subcutaneously to the sphincter cuff and may be adjusted by injection of saline to tighten the sphincter. Anecdotally, some dogs have not needed addition of saline to the port postoperatively, since the placement of the sphincter itself appears to provide enough support and occlusion of the urethra to allow continence to be maintained.

FIGURE 2. The artificial urethral sphincter. Cuff, tubing, and attached port with Huber injection needle (A). Radiographic image (right lateral view) of the sphincter after placement around the urethra of a dog (B). Images courtesy of Mary McLoughlin, DVM, MS, DACVS, The Ohio State University.

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Colposuspension

Transobturator Vaginal Tape

In animals with a normally positioned bladder, rises in intra-abdominal pressure transmit to the proximal urethra as well as the bladder, preventing urine leakage. In animals with a caudally positioned or “pelvic” bladder, the proximal urethra is not within the abdominal cavity, and this pressure is not exerted on the urethra. This creates a pressure gradient from bladder to urethra and leads to urine leakage.

The Hammock theory describes stress urinary incontinence in women as related to weakening of the structures supporting the bladder and urethra where they are both subject to intraabdominal pressures. In humans, this is often managed with procedures that stabilize the mid-urethra during increases in abdominal pressure, using a surgically placed tape to pull the vagina and urethra against the pubis.

Colposuspension is a procedure in which the lateral vaginal walls are attached to the prepubic tendon, thus drawing the bladder neck and proximal urethra further into the abdomen. This has been found to have variable success (53%) but has a high failure rate because of breakdown of the attachment to the pelvic ligament. An 11.3% complication rate has been reported related to urine retention and dysuria.20

In women, there have been significant complication rates with these procedures, frequently requiring removal of the tape. This procedure has been adapted for use in dogs with some success; however, its use is not widespread. Concerns about similar complications to those seen in women may be partially responsible.23 Additional studies evaluating larger numbers of dogs and long-term followup are needed.

Urethropexy

PREVENTION

Urethropexy repositions the bladder cranially by anchoring the proximal urethra to the prepubic tendon. Similar to colposuspension, this increases transmission of intra-abdominal pressure increases to the urethra as well as the bladder and bladder neck, preventing a negative pressure gradient into the outflow tract.

Of course, the best management for UI would involve efforts to prevent it. It is well known that UI is most common in dogs that are spayed or neutered; however, the exact mechanism and relationship to estrogen and testosterone decline is unclear. A number of studies have evaluated the relationship of UI and age at spay or neuter. The results have been somewhat disparate, but there is general agreement that the risk of UI increases if a female dog is spayed before 3 months of age.

Success has been reported to be similar to colposuspension, but with shorter efficacy, likely because of avulsion of the urethropexy from the prepubic tendon. Urethropexy may have an increased complication rate (21%) compared with colposuspension, with surgical revision being required in animals with urethral obstruction.21

Combined UrethropexyColposuspension A recent report of a combined technique of urethropexy and colposuspension revealed an improved success rate (70%) and durability compared with either procedure alone, as well as fewer complications (10%).22

URETHRAL INCOMPETENCE IN DOGS

In a recent study, I found that the age of ovariohysterectomy (OVH) did not appear to affect risk of development of UI in dogs with an expected adult weight of <15 kg. Smaller breeds are known to be at lower risk of urinary incontinence, and it appears that risk is not affected by age of spay. In larger breeds—dogs with an expected adult weight >15 kg—there is a decreased risk of UI with every month delay in OVH. The larger the dog, the more pronounced this alteration in risk becomes. The decision of when to spay a dog can be challenging. The risks of delaying spay

CONTINUING EDUCATION

surgery, such as increased chance of mammary carcinoma, and benefits, like a lower risk of UI, should be openly discussed with the owner and tailored to the individual. Some evidence suggests that obesity may increase the risk of incontinence in spayed female dogs; however, appropriate investigation into the contribution of body condition score is lacking. At this time, the contribution of obesity to the development of incontinence is unknown.

Glossary DES diethylstilbestrol FSH follicle stimulating hormone GnRH gonadotropin-releasing hormone LH luteinizing hormone OVH ovariohysterectomy PPA phenylpropanolamine UI urethral incompetence USMI urethral sphincter mechanism incompetence

REFERENCES 1. Byron JK, March PA, Chew DJ, DiBartola SP. Effect of phenylpropanolamine and pseudoephedrine on the urethral pressure profile and continence scores of incontinent female dogs. J Vet Intern Med 2007;21(1):47-53. 2. Scott L, Leddy M, Bernay F, Davot JL. Evaluation of phenylpropanolamine in the treatment of urethral sphincter mechanism incompetence in the bitch. J Small Anim Pract 2002;43(11):493-496. 3. Peterson KL, Lee JA, Hovda LR. Phenylpropanolamine toxicosis in dogs: 170 cases (2004-2009). JAVMA 2011;239(11):1463-1469. 4. Segev G, Westropp JL, Kulik C, Lavy E. Changes in blood pressure following escalating doses of phenylpropanolamine and a suggested protocol for monitoring. Can Vet J 2015;56(1):39-43. 5. Hill K, Jordan D, Ray J, et al. Medical therapy for acquired urinary incontinence in dogs. Int J Pharm Compd 2012;16(5):369-375. 6. Kitta T, Haworth-Ward DJ, Miyazato M, et al. Effects of ovariectomy and estrogen replacement on the urethral continence reflex during sneezing in rats. J Urol 2011;186(4):1517-1523. 7. Dore M, Chevalier S, Sirois J. Estrogen-dependent induction of cyclooxygenase-2 in the canine prostate in vivo. Vet Pathol 2005;42(1):100-103. 8. Sontas HB, Dokuzeylu B, Turna O, Ekici H. Estrogen-induced myelotoxicity in dogs: A review. Can Vet J 2009;50(10):1054-1058. 9. Nendick PA, Clark WT. Medical therapy of urinary incontinence in ovariectomised bitches: a comparison of the effectiveness of diethylstilboestrol and pseudoephedrine. Aust Vet J 1987;64(4):117-118. 10. Mandigers RJ, Nell T. Treatment of bitches with acquired urinary incontinence with oestriol. Vet Rec 2001;149(25):764-767. 11. Reichler IM, Hung E, Jochle W, et al. FSH and LH plasma levels in bitches with differences in risk for urinary incontinence. Theriogenology 2005;63(8):2164-2180. 12. Reichler IM, Jochle W, Piche CA, et al. Effect of a long acting GnRH analogue or placebo on plasma LH/FSH, urethral pressure profiles and clinical signs of urinary incontinence due to sphincter mechanism incompetence in bitches. Theriogenology 2006;66(5):1227-1236. 13. Reichler IM, Hubler M, Jochle W, et al. The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs. Theriogenology 2003;60(7):1207-1216. 14. Creed KE. Effect of hormones on urethral sensitivity to phenylephrine in normal and incontinent dogs. Res Vet Sci 1983;34(2):177-181. 15. Hamaide AJ, Grand JG, Farnir F, et al. Urodynamic and morphologic changes in the lower portion of the urogenital tract after administration of estriol alone and in combination with phenylpropanolamine in sexually intact and spayed female dogs. Am J Vet Res 2006;67(5):901-908. 16. Barth A, Reichler IM, Hubler M, et al. Evaluation of long-term effects of endoscopic injection of collagen into the urethral submucosa for treatment of urethral sphincter incompetence in female dogs: 40 cases (1993-2000). JAVMA 2005;226(1):73-76.

17. Byron JK, Chew DJ, McLoughlin ML. Retrospective evaluation of urethral bovine cross-linked collagen implantation for treatment of urinary incontinence in female dogs. J Vet Intern Med 2011;25(5):980-984. 18. Rose SA, Adin CA, Ellison GW, et al. Long-term efficacy of a percutaneously adjustable hydraulic urethral sphincter for treatment of urinary incontinence in four dogs. Vet Surg 2009;38:747-753. 19. Reeves L, Adin C, McLoughlin M, et al. Outcome after placement of an artificial urethral sphincter in 27 dogs. Vet Surg 2013;42:12-18. 20. Holt PE. Long-term evaluation of colposuspension in the treatment of urinary incontinence due to incompetence of the urethral sphincter mechanism in the bitch. Vet Rec 1990;127(22):537-542. 21. White RN. Urethropexy for the management of urethral sphincter mechanism incompetence in the bitch. J Small Anim Pract 2001;42(10):481-486. 22. Martinoli S, Nelissen P, White RA. The outcome of combined urethropexy and colposuspension for management of bitches with urinary incontinence associated with urethral sphincter mechanism incompetence. Vet Surg 2014;43(1):52-57. 23. Claeys S, de Leval J, Hamaide A. Transobturator vaginal tape inside out for treatment of urethral sphincter mechanism incompetence: preliminary results in 7 female dogs. Vet Surg 2010;39(8):969-979.

Julie K. Byron

Julie K. Byron, DVM, MS, DACVIM, is an associate professor â&#x20AC;&#x201C; clinical at The Ohio State University College of Veterinary Medicine. Her primary area of interest and research is lower urinary tract disease, specifically urinary incontinence and functional obstruction. She has written more than 13 book chapters on the diagnosis and treatment of lower urinary tract disease, and she has authored numerous research articles on diagnosis and treatment of urinary incontinence. She received her veterinary degree in 1998 from The Ohio State University and completed a small animal internal medicine residency there in 2004. She has worked in both private and academic practice and was a faculty member at the University of Illinois from 2005 to 2011.

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Introducing Spark! Your Veterinary News, Your Veterinary Life The newest addition to the NAVC publishing group, Spark! is an online video channel providing weekly programming for veterinary professionals, including coverage of breaking news, industry trends, and lifestyle stories within the veterinary community. Spark! will help veterinarians build a better practice by discussing topics such as marketing strategies and successful practice models for the future, as well as providing updates on new products, mergers, and animal health news. Spark! will also be featuring uplifting, inspirational and wellnessfocused stories to help bring balance to your working life.

■B e sure to like NAVC on Facebook to catch all of Spark!’s new content, and check out the latest videos now by visiting NAVC.com/Spark.

Innovation,

Science & B E YO N D

JUNE 8–10

2017

Gaylord National Resort and Convention Center National Harbor, MD

Don’t miss out on the veterinary profession’s premier internal medicine continuing education event. Register by April 30, 2017 to get 15% off full general registration using code 2017VMA.

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URETHRAL INCOMPETENCE IN DOGS

NEW PRODUCT GALLERY

The NAVC introduces the 2017 New Product Gallery Be the first to check out revolutionary products that will enhance the way you practice! The NAVC Conference 2017 featured 20 products in its New Product Gallery. Eligible products were selected by an NAVC committee made up of industry veterinarians and veterinary technicians. They launched or will launch between July 2016 and July 2017.

40-Watt CO2 Surgical Laser by Cutting Edge Laser Technologies

Catego for Cats by Ceva Animal Health, LLC

The Cutting Edge 40-watt CO2 Laser System sets a new standard in laser surgery by combining the advanced features of previous models with a new metal CO2 canister, improved user interface, and unprecedented 25-watt peak power SmartPulse technology.

Catego is a new, powerful monthly flea and tick preventative made specifically for cats weighing >1.5 lb and older than 8 weeks. It kills fleas within 6 hours and, on the day of application, is 97% efficacious in killing fleas within 3 hours. It also kills all life stages of ticks through contact for a full month.

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BabelVet by Babel Bark Powered by patented fitness monitoring technology, BabelVet measures activity trends and includes a mobile app that captures weight changes, medical dosage frequencies, and comprehensive nutritional information for more than 700 food brands. With BabelVet, veterinarians can engage more closely with clients between visits to improve satisfaction, increase return appointments, and grow their practice through client loyalty. babelbark.com

Bravecto by Merck Animal Health Bravecto (fluralaner topical solution) provides 12 weeks of flea and tick protection with a single treatment. Bravecto is proven safe for cats 6 months and older and weighing ≥2.6 lb. The treatment comes in a unique Twist’n’Use tube, making application easy because the cap doesn’t come off.

CYTOPOINT by Zoetis CYTOPOINT is a new injectable monoclonal antibody therapy that provides fast, effective relief to help improve the long-term quality of life for dogs with atopic dermatitis and their owners. cytopoint.com

Effitix Plus by Virbac Effitix offers easy, convenient application that stops existing flea and tick infestations and prevents establishment of new infestations. The product starts working on contact, meaning fleas do not have to bite to die. It is waterproof for up to 4 weeks, making it long-lasting flea, flea egg, flea pupae, flea larvae, tick and mosquito control. Effitix prevents reinfestation for one month. virbacvet.com

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ENTYCE by Aratana Therapeutics Inc ENTYCE (capromorelin oral solution) is a flavored liquid prescription product administered orally using the provided syringe. A selective ghrelin receptor agonist, it mimics ghrelin, the naturally occurring “hunger hormone” produced in the stomach that is integral to the regulation of food intake. Ghrelin binds to receptors in the hypothalamus, initiating signaling cascades to trigger appetite. aratana.com/therapeutics/inappetence

GALLIPRANT by Elanco Animal Health GALLIPRANT (grapiprant tablets) is a first-inclass, non-cyclooxygenase–inhibiting prostaglandin receptor antagonist that specifically targets the EP4 receptor. GALLIPRANT directly blocks the key receptor involved in canine osteoarthritis pain and inflammation. GALLIPRANT provides convenient, once-aday dosing with whole or half tablets based on weight. elanco.us/galliprant/vet

Hill’s Prescription Diet k/d+Mobility Prescription Diet k/d + Mobility is formulated to improve mobility and increase vitality and alertness in older pets with chronic kidney disease (CKD). k/d + Mobility foods are designed to stimulate the appetites of pets with CKD, ensuring optimal caloric intake critical for muscle mass. hillsvet.com/en/us/home

Itrafungol by Elanco Animal Health

MyVet i72w Elevating X-Ray System The MyVet table system is a revolutionary veterinary elevating DR X-Ray table system that delivers silent elevation to fulfill comfort and stability. The MyVet table is cost effective and designed to improve patient workflow in your veterinary practice. MyVet myvetimaging.com/vettable

Nobivac Canine Flu Bivalent by Merck Animal Health The U.S. Department of Agriculture has approved a license for Nobivac Canine Flu Bivalent – the first vaccine to aid in the control of disease associated with both canine influenza virus (CIV) H3N2 and canine influenza virus H3N8. Nobivac Canine Flu Bivalent is recommended for healthy dogs 7 weeks of age or older as an aid in the control of disease associated with canine influenza virus H3N8 and canine influenza virus H3N2. nobivac.com/Default.aspx

NOCITA by Aratana Therapeutics Inc NOCITA (bupivacaine liposome injectable suspension), a is a new, long-acting local anesthetic for local postoperative pain control for up to 72 hours after cranial cruciate ligament surgery in dogs. nocita.aratana.com

Onsior for Dogs by Elanco Animal Health

A flavored new way to fight feline dermatophytosis, Itrafungol is indicated for the treatment of dermatophytosis caused by Microsporum canis in cats.

Onsior for Dogs is indicated for pain and inflammation associated with soft tissue surgery for dogs weighing ≥5.5 lb and aged ≥4 months for up to a maximum of 3 days.

elancovet.com

us.onsior.com

NEW PRODUCT GALLERY

Now available from Virbac

Your solution for the recuperation support of dogs and cats.

Palatable liquid formulation. Distinct formulas for feline and canine care.

Deliver vital nutrients to support early and progressive recuperation and promote eating and drinking of recovering animals. REBOUNDTM Recuperation Formula is designed speciﬁcally to support recovery and offers a well-balanced, low-calorie formulation rich in vitamins and minerals. • Contains essential nutrients—vitamins, minerals, amino acids, and fatty acids • Delivers key ingredients for recuperation—arginine, taurine, and omega-6 and omega-3 fatty acids • Includes prebiotics to support gastrointestinal health Jump-start the gut with REBOUND Recuperation Formula. To order, talk to your distributor or Virbac representative, or call 1-844-4-VIRBAC (1-844-484-7222). © 2016 Virbac Corporation. All Rights Reserved. REBOUND is a trademark of Virbac Corporation. 12/16 17134

NEW PRODUCT GALLERY

Purina Pro Plan Veterinary Diets NeuroCare

Royal Canin Veterinary Diet Canine Selected Protein Adult KO

The first and only diet to nutritionally manage dogs with idiopathic epilepsy when fed as an adjunct to veterinary therapy, NeuroCare also helps nutritionally manage dogs with cognitive dysfunction syndrome. The diet is formulated with medium-chain triglyceride oil.

Canine Selected Protein Adult KO joins Royal Canin’s extensive line of diets for the management of adverse food reactions in dogs with dermatologic and/or gastrointestinal signs. Adult KO is formulated with kangaroo and oats, which are rarely associated with food sensitivities in dogs.

purinaproplanvets.com

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REBOUND Recuperation Formula by Virbac

Samsung PT10V by scil animal care, a division of Henry Schein Animal Health

REBOUND Recuperation Formula offers a palatable, well-balanced, low-calorie liquid formulation rich in vitamins and minerals. It is designed specifically to support early and progressive recuperation and promote eating and drinking of recovering dogs and cats. virbacvet.com

scil’s new blood chemistry analyzer from Samsung is the biggest little innovation in decades. Microfluidic technology provides accurate results from an extremely small sample in less than 10 minutes. It’s compact, easy to operate, and virtually maintenance free. scilvet.us

Royal Canin Veterinary Diet Feline ULTAMINO Feline ULTAMINO is a breakthrough diet for adult cats suffering from adverse food reaction or inflammatory bowel disease/ chronic enteropathy. Feline ULTAMINO is formulated with an extensively hydrolyzed protein source in which 95% of peptides are below 1 kDa in size and 88% are free amino acids. ultamino.royalcanin.com

Talkingvet Cloud Dictation by Talkingvet If you are transitioning to “paper-light” medical records, documenting patient care can become very time consuming. Talkingvet Cloud speech recognition and dictation can make this transition less frustrating and more efficient. We offer the highest-quality systems using stateof-the-art technology. talkingvet.com/vetCloud_trial

The Joys of Spring! Adopt-A-Manatee® and Help Protect Them

Call 1-800-432-JOIN (5646) savethemanatee.org Photo © Cora Berchem

NEW PRODUCT GALLERY

The New Product Gallery is limited to 20 exhibitors and requires an application and acceptance. Check out navc.com/conference/new-product-gallery for more information!

NUTRITION NOTES

ACVN NUTRITION NOTES

Diets and the Dermis: Nutritional Considerations in Dermatology Justin Shmalberg, DVM, DACVN, DACVSMR University of Florida College of Veterinary Medicine shutterstock.com/Christian Mueller

The American College of Veterinary Nutrition (acvn.org) and Today’s Veterinary Practice are delighted to bring you the Nutrition Notes column, which provides the highest-quality, cutting-edge information on companion animal nutrition, written by the ACVN’s foremost nutrition specialists. The primary objectives of the ACVN are to: • Advance the specialty area of veterinary nutrition • I ncrease the competence of those practicing in this field •E stablish requirements for certification in veterinary nutrition •E ncourage continuing education for both specialists and general practitioners • Promote evidence-based research •E nhance dissemination of the latest veterinary nutrition knowledge The ACVN achieves these objectives in many ways, including designating specialists in animal nutrition, providing continuing education through several media, supporting veterinary nutrition residency programs, and offering a wide array of resources related to veterinary nutrition, such as this column.

Dermatologic patients are often managed with topical and systemic pharmacologic therapies, but nutrition should be evaluated in all animals presenting with skin disease. Nutritional deficiencies and excesses are rarely the underlying cause of a patient’s clinical signs, but nutritional modifications often reduce the severity of such signs.

NUTRIENTS The influence of nutrition in dermatologic conditions is explained by critical nutrients that affect keratinization, cellular barriers, and turnover, as well as sebum production and composition. Protein and amino acids provide substrates for keratinization, pigmentation, and hair growth. A substantial portion of daily protein requirements is used for skin and hair production.1

• Phenylalanine and tyrosine are precursors to melanin, and relative deficiencies may induce reddening of black coats (Figure 1).2 • Methionine and cysteine, the primary sulfurcontaining amino acids, are incorporated into hair in large amounts and may be the “limiting” amino MARCH/APRIL 2017

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• Vitamin E is the primary antioxidant in the cell membrane and can refer to any of 4 tocopherols and 4 tocotrienols. Alphatocopherol is the form with greatest activity in cells, although others may be added to commercial diets as natural preservatives. Experimental deficiency causes alopecia, seborrhea, and increased cutaneous infections.3

FIGURE 1. This middle-aged domestic shorthair cat displays reddening of the fur, which may prove responsive to increased dietary protein and/or supplementation with tyrosine or phenylalanine.

acids (ie, those which limit protein synthesis) in some pet diets. Deficiency of these amino acids may reduce hair growth and increase hair fragility.3,4

• Proline is a nonessential amino acid critical to collagen formation in the skin. Protein deficiency would be expected to have a deleterious effect on skin strength.3 Polyunsaturated fatty acids provide substrate for the production of sebum, which protects the dermis and improves coat quality.a

• Linoleic acid, an 18-carbon omega-6 fatty acid, appears to be most important for this effect.5–7 • Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may reduce inflammation secondary to allergic disease in affected dogs and cats.8 Several vitamins play critical roles in skin health.

• Vitamin A is a group of fat-soluble retinoids critical for epidermal differentiation and normal sebum production. Deficiency is rare, but unlike dogs, cats cannot convert beta-carotene to retinol.3

• B vitamins participate in many biochemical reactions throughout the body, and experimental deficiencies have caused a variety of skin lesions. Vitamin B3 (niacin) and B5 (pantothenic acid) supplementation above normal recommended allowances has reduced transepidermal water loss in dogs and contributed to the integrity of the stratum corneum.9 Copper serves as a cofactor in enzymatic conversion of tyrosine to melanin. Deficiency can cause changes in pigmentation. Zinc is critical for the transition of nucleated epidermal cells to anucleate squamous cells in the stratum corneum, and deficiency induces parakeratosis. Zinc also participates in essential fatty acid conversion.3

Commercial diets conforming to Association of American Feed Control Officials recommendations should be replete in all of the nutrients above. However, several factors could increase the relative risk for deficiencies over time:

• Malabsorptive disorders, such as exocrine pancreatic insufficiency, inflammatory bowel disease, and small intestinal bacterial overgrowth • Home-prepared diets without dietary analysis or supplementation • Diets labeled for intermittent or supplemental feeding when fed for an extended time • High dietary phytate concentration, which

• Vitamin C is synthesized in dogs and cats from glucose (unlike in humans) and is necessary for collagen synthesis and cross-linking.

a For more information on the roles of polyunsaturated fatty acids, see “Dietary Fatty Acids in Dogs & Cats” by Dr. Catherine Lenox in the September/October 2016 issue of Today’s Veterinary Practice on tvpjournal.com.

ACVN NUTRITION NOTES

FIGURE 2. Zinc-responsive dermatosis syndrome 1 in a young Siberian husky. Courtesy Dr. Dunbar Gram.

NUTRITION NOTES

binds minerals such as zinc, or excesses of some minerals that adversely affect absorption of others

CLINICAL CONDITIONS Several common dermatologic signs may prove nutritionally responsive (Box 1). The primary cause may not always be identified, but a skin biopsy is often prudent to better characterize the lesion and to decide how best to modify a patient’s diet. Knowledge of characteristic or common clinical conditions informs the possible use of nutritional intervention, and a response to a particular nutritional therapy is often used to confirm a presumptive diagnosis.

Zinc-Related Dermatoses In dogs, zinc-related dermatoses are characterized by parakeratotic hyperkeratosis of the face and feet, with resultant crusts and lesions (Figure 2).10 These dermatoses include lethal acrodermatitis in bull terriers and zinc-responsive dermatosis syndromes I and II. Characteristics of these conditions are presented in Box 2. Serum and hair testing are unreliable measures of zinc status, so supplementation of dogs with characteristic lesions, especially in breeds

TABLE 1 Concentration of Elemental Zinc in Different Oral Supplements* ZINC SUPPLEMENT

MG ZN/100 MG POWDER

Zinc gluconate

Zinc methionine

Zinc sulfate

*A starting dose of 2 to 3 mg Zn/kg is often recommended. Many supplements are sold according to the amount of elemental zinc.

associated with zinc-responsive dermatosis syndrome I, is advised. Zinc gluconate is well tolerated and efficacious, but some clinicians prefer zinc methionine because of increased availability. The relative amount of elemental zinc for different supplements is found in Table 1. Vomiting is the most common, and generally dosedependent, side effect of zinc supplementation, and several forms may need to be tried at varying doses to assess individual tolerance.

BOX 2. Characteristics of Zinc-Related Dermatoses Lethal acrodermatitis of bull terriers11 • Complete dysfunction of zinc metabolism • I mpaired growth, eating difficulty, crusting and scaling of the feet and pads, and splayed digits

BOX 1. Dermatologic Signs That May Respond to Nutritional Management • Pruritus • Recurrent pyoderma • Dull hair coat • Epidermal scaling • Urticaria • Keratinization disorders • Concurrent gastrointestinal signs • Coat color change • Chronic otitis • Miliary dermatitis (in cats) • Alopecia

• Unresponsiveness to zinc supplementation • High mortality rate Zinc-responsive dermatosis syndrome I3,10 • Results from a genetic defect that reduces zinc absorption • I s more prevalent in Northern breed dogs (huskies, malamutes) •R equires lifetime oral zinc supplementation (2 to 10 mg elemental zinc per kg is empirically recommended)4,10 Zinc-responsive dermatosis syndrome 23,12 • Associated with rapidly growing large-breed dogs or dogs receiving diets high in phytates and other zinc-binding compounds •R esolves after a change to a diet with greater zinc concentrations and/or with reduced zinc-binding compounds

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Vitamin A–Responsive Dermatosis

Hepatocutaneous Syndrome

Dermatosis responsive to vitamin A is a rare, presumably heritable, condition of dogs. Lesions are characterized by abnormal cornification, hyperkeratotic plaques, abnormal sebum, epidermal scaling, alopecia, and secondary pyoderma (Figure 3). Biopsy specimens are consistent with orthokeratotic and follicular hyperkeratosis.13 Cocker spaniels are the most affected breed, but other breeds are also rarely affected.14 Oral retinol (vitamin A) is reported to ameliorate clinical signs, but the optimal dose is unknown (authors have suggested 10,000 IU/dog q24h or 1000 IU/kg q24h).4,13 Synthetic retinoids have been reported in the treatment of primary keratinization disorders but are unlikely to be necessary in cases of true vitamin A dermatosis; moreover, the side effect profiles of these drugs warrant their use only by those familiar with their administration.

This condition, also called migratory necrolytic erythema or superficial necrolytic dermatitis, is diagnosed infrequently in dogs and, very rarely, cats with liver dysfunction, chronic phenobarbital exposure, diabetes mellitus, or pancreatic tumors (such as glucagonomas).4,15,16 The syndrome has been reported in older dogs of many breeds, and evidence exists for a possible heritable predisposition in shih tzus.16

FIGURE 3. Vitamin A–responsive dermatosis lesions in cocker spaniels. Courtesy UF Veterinary Dermatology.

ACVN NUTRITION NOTES

Elevated alkaline phosphatase and microcytosis are laboratory findings reported in case series, but liver values may be normal. Histologic lesions are unique with parakeratotic hyperkeratosis (“red” layer), pale and edematous keratinocytes in the stratum granulosum and stratum spinosum

FIGURE 4. Hepatocutaneous syndrome lesions of the nasal planum and feet with characteristic severe crusts and secondary inflammation. Courtesy UF Veterinary Dermatology.

NUTRITION NOTES

(“white” layer), and stratum basale hyperplasia (“blue” layer). Distribution of lesions is similar to that in zinc dermatoses but of increased severity, and affected animals generally display nonspecific systemic signs (lethargy, inappetence) or risk factors described above (Figure 4). Plasma amino acid levels are often below reference intervals.17 Hepatic ultrasonography may reveal diffuse mottling or a reportedly characteristic “Swiss cheese” or “honeycomb” appearance. Median survival times with supportive treatments are less than 6 months.16 Reported treatments include16:

• Parenteral amino acid infusions (weekly, adjusted according to lesion response) • Diets with moderate to high amounts of digestible dietary protein (>75 g/Mcal) • Hepatic antioxidants (vitamin E, silybin, glutathione precursors) • Oral zinc • Essential fatty acids

the risk for the condition, as the degree of fatty acid oxidation is likely correlated to risk.20

Diet-Related Dermatoses These disorders are characterized by cutaneous manifestations of food intolerance or food allergy. Adverse reactions to food may also cause gastrointestinal, respiratory, or systemic signs, which are reviewed elsewhere.21,22 Owners commonly ascribe dermatologic symptoms to food allergy, but atopic dermatitis (AD; see Nutritional Considerations in Diagnosing and Managing Atopic Dermatitis) is more prevalent. Owners also often insist that dietary modification be made even when a dietary origin of clinical signs is unlikely. Food intolerance could result from many individual predispositions, but by definition, it is nonimmunologic in origin.22 Gastrointestinal signs are most commonly ascribed to food intolerance.

• Anti-inflammatory glucocorticoids Parenteral amino acid infusions appear to have the greatest effect on the condition, and one report suggested a reduced frequency of administration with concurrent parenteral lipid administration (2.4 g/kg amino acids + 1.4 g/kg lipid).18 The underlying cause, if identified, should be concurrently managed. High-protein diets should not be given to dogs with hepatic encephalopathy.

Vitamin E Deficiency in Cats This condition is associated with diets high in polyunsaturated fats, such as canned seafood, that are deficient in vitamin E. Affected cats display reluctance to move and pain and are often febrile. Pansteatitis is evident grossly, and ceroid deposits within affected subcutaneous fat are characteristic of this condition (Figure 5).19 The vitamin E requirement is mildly increased as the polyunsaturated fat concentration of the diet increases (<5 IU per g of marine oil).20 Improper food storage, heat processing, or inadequate vitamin E in high-fat diets all increase

FIGURE 5. Nodular pansteatitis of the mesenteric fat (top) and subcutaneous fat (bottom). Courtesy of Mike Schaer, DVM, DACVIM, DACVECC, University of Florida.

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Dermatologic manifestations of food intolerance are presumptively related to dietary compounds that worsen the response to another disease, such as AD. Examples may include38:

• Foods naturally high in histamine (or the amino acid precursor l-histidine), such as animal meats (eg, pork and beef—histidine), fish, tomatoes, mushrooms, spinach (histamine) • Foods containing other amines, such as tyramine: cured or processed meats, fermented foods, dried or overripe fruits Some foods may increase endogenous histamine release via activation of enzymatic pathways of histamine production.

Trials of diets with different primary, even if not novel, ingredients should be sufficient to determine whether food intolerance is responsible for cutaneous signs. Food allergy is an inappropriate immunologic response to dietary antigens.21 Clinical signs may include erythema, epidermal scaling, patchy alopecia, miliary dermatitis (in cats), recurrent pyoderma, and urticaria (Figure 6). Many dogs with food allergy display perianal pruritus.24 Concurrent gastrointestinal signs are variably present. Signs are often nonseasonal and unresponsive to immunosuppressive corticosteroids.

A physical examination is generally insufficient to distinguish atopic from food-associated

Nutritional Considerations in Diagnosing and Managing Atopic Dermatitis Atopic dermatitis (AD) produces clinical signs and lesions often indistinguishable from those of food allergy (Figure 7). However, several nutritional modifications have been shown or suggested to influence disease severity in dogs or cats.

gamma-linolenic acid (DGLA). 26 Borage seed, evening primrose, and black currant seed oil are common sources. Unlike other omega-6 fatty acids, DGLA impairs leukotriene formation from LOX enzymes and reduces inflammation.

Dietary food trials should be performed in all atopic animals. Food allergy is a comorbidity in many atopic patients, and food allergens may worsen atopy. 22,23 An 8-week trial is thought sufficient to identify 90% of cases. 24

Doses of 10 to 50 mg GLA/kg are reported, and the high end of the dose range is well tolerated by most dogs.

Essential fatty acids—primarily EPA and DHA— reduce the severity of pruritus and other signs in AD. 8,25 Clinical effects may not be documented for 4 to 12 weeks, as membrane incorporation of these dietary fats is required. EPA and DHA produce fewer inflammatory prostaglandins and leukotrienes by providing omega-3 substrate for cyclooxygenase and lipoxygenase (LOX) enzymes. 8 Fish oil (menhaden, sardine, anchovy) is the primary commercial source of EPA and DHA. Krill oil represents a possible alternative but has not been studied in dogs or cats and is more expensive. Algal oil is not recommended because it contains primarily DHA. A daily dose of 70 mg/kg combined EPA + DHA is recommended. This is equivalent to approximately 130 mg/kg 0.75 or about 1.5 mg per calorie fed. One standard fish oil capsule (300 mg EPA + DHA) per 10 lb body weight provides this dose. A cyclosporinesparing effect was reported at these doses. 25 Gamma-linolenic acid (GLA) is a plant-sourced omega-6 fatty acid that is converted to dihomo-

ACVN NUTRITION NOTES

•T his dose is equivalent to 20 to 100 mg/kg 0.75 or 0.2 to 1 mg GLA per calorie fed. •T he equivalent borage seed oil dose (20% to 25% GLA) is about 1 g per 10 lb body weight (high end). Combination products of fish oil and GLA-containing oils appear efficacious in clinical studies. Linoleic acid is a common plant-based omega-6 fatty acid. High concentrations are found in safflower and sunflower oils. Elevated doses are recommended in humans with skin disease because of positive effects on the epidermal barrier. Very high doses (1.4 g/kg) improved seborrhea in dogs, 27 but this dose would increase a patient’s caloric intake by 25% and possibly unbalance a diet. Most commercial diets are replete in linoleic acid, so routine supplementation of such diets is not recommended. Owners may use other oils based on anecdotal reports, but objective information is limited. No studies show positive effects of dietary coconut oil on skin health in dogs. Flax seed does not adequately increase EPA or DHA because of reduced conversion in dogs and cats, and it is not recommended for atopy. 8 Flax seed did improve coat

NUTRITION NOTES

dermatopathy, and an estimated 30% of dogs and cats with food allergy have other dermatologic comorbidities.21 Pathophysiology of food allergy may be mediated by IgE, antibody-antigen complexes, or cell-mediated immunity. Dogs and cats of all breeds are affected, and Siamese cats may be overrepresented.19 Some diets contain variable amounts of storage mites, which trigger allergic reactions in sensitized animals. Studies have not yet determined differences in response to variable diet types.24 FIGURE 6. Severe food allergy in a Labrador retriever with pruritus, bacterial pyoderma, and partial alopecia. Courtesy UF Veterinary Dermatology.

quality in dogs, but only transiently. 5 Conjugated linoleic acid failed to improve canine atopy. 28 The following nutritional approaches can be considered, but these have less evidentiary support. • S upplementation of nutrients affecting the epidermal barrier. — A diet containing increased fortification of vitamin B5 (6.5×), vitamin B3 (24×), vitamin B6 (8×), choline (1.4×), and inositol (2.8×) fed to pregnant Labrador retrievers and their puppies reduced the incidence of atopy. 29

DIAGNOSIS AND TREATMENT Diagnosis and treatment of food allergy require a diet change. Three strategies may be used for a food trial.

— L actobacillus strains reduced AD symptoms in predisposed growing dogs and decreased clinical signs in adult dogs. 34,35 — P rebiotics and fecal microbiota transplantation have also been theorized to have similar benefits in animal patients. 36 Diets marketed for AD may produce differing clinical effects. Two of 3 tested diets marketed for canine AD produced significant improvement compared to a maintenance diet. Higher levels of EPA and DHA in these diets may explain the clinical effects. 37

— I n vitro effects of a combination of aloe vera, curcumin, vitamin C, and taurine decreased water diffusion across canine keratinocyctes 30 and are incorporated into a commercial therapeutic diet for AD. • H erbal extracts. — An extract containing the Chinese herbs Glycyrrhiza uralensis, Paeonia lactiflora, and Rehmannia glutinosa demonstrated a 25% reduction in pruritus in dogs compared with a 13% reduction in a placebo group, but this product is not available in the US market. 31 — Similar products are available but are not strongly regulated. 32 •V itamin E (8 IU/kg) improved AD scoring in dogs compared with placebo. 33 • Probiotics have been suggested to have immunomodulatory properties in AD.

FIGURE 7. Atopic dermatitis in a young Boston terrier with erythema, urticaria, self-excoriation, pruritus, and conjunctivitis.

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1. Hydrolyzed Diets

Dietary proteins are responsible for the inappropriate antigenic response in food allergies. Enzymatic hydrolysis reduces the size of these food antigens, thereby reducing IgE cross-linking and subsequent histamine response, as well as reducing epitopes for other immune responses.22,39 Diets vary in their degree of hydrolysis, and no product, except for prohibitively expensive pure amino acid diets, can guarantee complete reduction of antigenic stimulation.39

Lower-molecular-weight diets may be best for therapeutic trials, and higher-molecular-weight hydrolyzed diets could be tolerated in some dogs that respond to the initial trial. Dogs with a known allergy to a protein should likely avoid that protein, even when hydrolyzed, to avoid issues of incomplete hydrolysis.39 A diagnostic trial and improvement in clinical signs may require 8 to 12 weeks of feeding.24 Other foods and flavorants should be avoided during this period. Hydrolyzed diets are expensive and often lower in protein than other diets. These factors should be considered in the nutritional plan.

Mcal: 1000 kcal Met: Methionine

All dermatologic symptoms

Cys: Cysteine Tyr: Tyrosine Phe: Phenylalanine EPA: Eicosapentaenoic acid

Diet and supplement history

DHA: Docosahexaenoic acid GLA: Gamma-linolenic acid LA: Linoleic acid

Ensure adequacy of critical nutrients for dermis (amino acids, essential fats, vitamins A, C, E, B complex, copper, zinc)

Coat color change

Concurrent GI signs

Pruritus

Alopecia

Recurrent pyoderma

Dull hair coat

Urticaria

Epidermal scaling

Chronic otitis

Keratinization disorder Crusts Seborrhea

Miliary dermatitis

 Protein (>75 g/Mcal)  Met/Cys  Tyr/Phe

Avoid foods with histamine, tryptamine

Food trial (hydrolyzed or novel)

± Vit. E ( ≥ 8 IU/kg)

± probiotics ±  Bvitamins

70 mg/kg EPA+DHA and/or 30 mg/kg GLA

Check Zn ±  to 100 mg Zn/Mcal

 Dietary fat (>50 g/Mcal) or  LA

FIGURE 8. Treatment options based on a symptom-based algorithm for veterinary dermatology.

ACVN NUTRITION NOTES

Add Zn 2-10 mg/kg

 Vit A

≤ 1000 IU/kg

NUTRITION NOTES

2. Novel Protein Diets

These diets provide only proteins to which the specific patient has never been exposed.22 Appropriate use of such diets requires a careful and complete diet history. Over-the-counter diets containing previously rare proteins, such as alligator, kangaroo, pheasant, and bison, are available; therefore, clinicians should not assume that exotic proteins are novel for all patients. Contamination of diets during manufacturing may be more common than previously realized, and manufacturer quality control would contribute to response.40,41 3. Home-Prepared Diets

These diets are popular among some owners and can be used for novel protein trials. They may be subject to less unintentional contamination with other dietary proteins, and owners may elect such diets to feel like participants in the treatment plan. Patients with extensive diet histories or concurrent nutritional comorbidities (eg, pancreatitis) may require a custom protein or diet strategy. Unbalanced diets have historically been recommended to reduce ingredient numbers and possible antigenicity.42 Extended feeding (>4 weeks) of such diets might cause suboptimal levels of nutrients with effects on the epidermal barrier or turnover and immune status, but this has not been demonstrated in clinical studies. Extrusion, canning, baking, boiling, and feeding raw could have differential effects on antigenic structure. Therefore, anecdotal responses to such diets could be related to these different methods of preparation.43 Given the advantages and disadvantages for each strategy, two sequential strict food trials, using different diets, may be required to best eliminate food-responsive dermatopathies as differential diagnoses. Partial improvements should prompt clinicians to compare nutrient profiles in the event of intolerance or elevations of critical nutrients in the test diet (zinc, essential fatty acids, protein, B vitamins). Partial improvement may also suggest concurrent atopic or contact dermatitis

and should prompt additional screening for these conditions at the completion of the trial.

SUMMARY Nutritional modification clearly affects epidermal turnover, defensive barriers, inflammatory mediators, hair growth, and important features of normal and pathologic skin. Nutritional interventions can initially be made symptomatically and further refined once a definitive diagnosis is identified. A diagnostic flowchart of nutritional considerations for common dermatologic signs is provided in Figure 8. All interventions should, however, be predicated on a careful diet history and thorough assessment of current feeding strategies. References 1.

Hendriks WH, Tarttelin MF, Moughan PJ. Seasonal hair growth in the adult domestic cat (Felis catus). Compar Biochem Physiol Part A Physiol 1997; 116:29-35.

2. Anderson PJB, Rogers QR, Morris JG. Cats require more dietary phenylalanine or tyrosine for melanin deposition in hair than for maximal growth. J Nutr 2002; 132:2037-2042. 3. National Research Council. Nutrient Requirements of Dogs and Cats. Washington DC: National Academies Press, 2006. 4. Prelaud P, Harvey R. Nutritional dermatoses and the contribution of dietetics in dermatology In Pibot P, Biourge V,Elliott D (eds). Encyclopedia of Canine Clinical Nutrition. Aimargues, France: Aniwa SAS, 2006: pp 58-91. 5. Rees CA, Bauer JE, Burkholder WJ, et al. Effects of dietary flax seed and sunflower seed supplementation on normal canine serum polyunsaturated fatty acids and skin and hair coat condition scores. Vet Dermatol 2001; 12:111-117. 6. Marsh KA, Ruedisueli FL, Coe SL, et al. Effects of zinc and linoleic acid supplementation on the skin and coat quality of dogs receiving a complete and balanced diet. Vet Dermatol 2000; 11:277-284. 7. Kirby NA, Hester SL, Rees CA, et al. Skin surface lipids and skin and hair coat condition in dogs fed increased total fat diets containing polyunsaturated fatty acids. J Anim Physiol Anim Nutr 2009; 93:505-511. 8. Bauer JE. Therapeutic use of fish oils in companion animals. JAVMA 2011; 239:1441-1451. 9. Watson AL, Fray TR, Bailey J, et al. Dietary constituents are able to play a beneficial role in canine epidermal barrier function. Exp Dermatol 2006; 15:74-81. 10. White SD, Bourdeau P, Rosychuk RAW, et al. Zinc-responsive dermatosis in dogs: 41 cases and literature review. Vet Dermatol 2001; 12:101-109. 11. McEwan NA, McNeil PE, Thompson H, et al. Diagnostic features, confirmation and disease progression in 28 cases of lethal acrodermatitis of bull terriers. J Sm Anim Pract 2000; 41:501-507. 12. Van den Broek AHM, Thoday KL. Skin disease in dogs associated with zinc deficiency: a report of five cases. J Sm Anim Pract 1986; 27:313-323. 13. Hensel P. Nutrition and skin diseases in veterinary medicine. Clin Dermatol 2010; 28:686-693. 14. Ihrke PJ, Goldschmidt MH. Vitamin A-responsive dermatosis in the dog. JAVMA 1983; 182(7):687-690. 15. Byrne KP. Metabolic epidermal necrosis-hepatocutaneous syndrome. Vet Clin North Am Sm Anim Pract 1999; 29(6):1337-1355. 16. Hall-Fonte DL, Center SA, McDonough SP, et al. Hepatocutaneous syndrome in Shih Tzus: 31 cases (1996â&#x20AC;&#x201C;2014). JAVMA 2016; 248:802813.

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PEER REVIEWED 20. Hendriks WH, Wu YB, Shields RG, et al. Vitamin E requirement of adult cats increases slightly with high dietary intake of polyunsaturated fatty acids. J Nutr 2002; 132:1613S-1615S.

Justin Shmalberg

Justin Shmalberg, DVM, DACVN, DACVSMR, is a clinical associate professor of integrative medicine at University of Florida College of Veterinary Medicine. His service specializes in the incorporation of nutrition, rehabilitation, hyperbaric oxygen therapy, and acupuncture with conventional care; he holds certifications in acupuncture and herbal medicine. Dr. Shmalberg’s research interests include nutritional oncology, sports and rehabilitative nutrition, evaluations of new small animal dietary trends, and the safety and efficacy of Chinese herbal products. He received his DVM from University of WisconsinMadison. Dr. Shmalberg completed an internship in veterinary acupuncture at University of Florida along with a residency in small animal clinical nutrition.

21. Verlinden A, Hesta M, Millet S, et al. Food allergy in dogs and cats: a review. Crit Rev Food Sci Nutr 2006; 46:259-273. 22. Gaschen FP, Merchant SR. Adverse food reactions in dogs and cats. Vet Clin North Am Sm Anim Pract 2011; 41:361-379. 23. Pucheu-Haston CM, Bizikova P, Eisenschenk MNC, et al. Review: The role of antibodies, autoantigens and food allergens in canine atopic dermatitis. Vet Dermatol 2015; 26:115-130. 24. Olivry T, DeBoer DJ, Favrot C, et al. Treatment of canine atopic dermatitis: 2015 updated guidelines from the International Committee on Allergic Diseases of Animals (ICADA). BMC Vet Res 2015; 11:210. 25. Müller MR, Linek M, Löwenstein C, et al. Evaluation of cyclosporinesparing effects of polyunsaturated fatty acids in the treatment of canine atopic dermatitis. Vet J 2016; 210:77-81. 26. Saevik BK, Bergvall K, Holm BR, et al. A randomized, controlled study to evaluate the steroid sparing effect of essential fatty acid supplementation in the treatment of canine atopic dermatitis. Vet Dermatol 2004; 15:137-145. 27. Campbell KL, Uhland CF, Dorn GP. Effects of oral sunflower oil on serum and cutaneous fatty acid concentration profiles in seborrheic dogs. Vet Dermatol 1992; 3:29-35.

17. Outerbridge CA, Marks S, Rogers QR. Plasma amino acid concentrations in 36 dogs with histologically confirmed superficial necrolytic dermatitis. Vet Dermatol 2002; 13:177-186. 18. Bach JF, Glasser SA. A case of necrolytic migratory erythema managed for 24 months with intravenous amino acid and lipid infusions. Can Vet J 2013; 54:873-875. 19. Mueller RS, Dethioux F. Nutritional dermatoses and the contribution of dietetics in dermatology. In Pibot P, Biourge V, Elliott D (eds). Encyclopedia of Feline Clinical Nutrition. Aimargues, France: Aniwa SAS, 2008: pp 51-75.

28. Noli C, Carta G, Cordeddu L, et al. Conjugated linoleic acid and black currant seed oil in the treatment of canine atopic dermatitis: a preliminary report. Vet J 2007; 173:413-421. 29. van Beeck FL, Watson A, Bos M, et al. The effect of long-term feeding of skin barrier-fortified diets on the owner-assessed incidence of atopic dermatitis symptoms in Labrador retrievers. J Nutr Sci 2015; 4:e5. 30. Fray TR, Watson AL, Croft JM, et al. A combination of aloe vera, curcumin, vitamin C, and taurine increases canine fibroblast migration and decreases tritiated water diffusion across canine keratinocytes in vitro. J Nutr 2004; 134:2117S-2119S. 31. Nagle TM, Torres SM, Horne KL, et al. A randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of a Chinese herbal product (P07P) for the treatment of canine atopic dermatitis. Vet Dermatol 2001; 12:265-274. 32. Shmalberg J. Surveying supplements: current trends, research, and recommendations. Today’s Veterinary Practice 2014; 4(3):79-84. 33. Kapun AP, Salobir J, Levart A, et al. Vitamin E supplementation in canine atopic dermatitis: improvement of clinical signs and effects on oxidative stress markers. Vet Rec 2014; 175:560. 34. Marsella R, Santoro D, Ahrens K. Early exposure to probiotics in a canine model of atopic dermatitis has long-term clinical and immunological effects. Vet Immunol Immunopathol 2012; 146:185-189.

INNOVATION

AWARDS

35. Kim H, Rather IA, Kim H, et al. A double-blind, placebo controlledtrial of a probiotic strain Lactobacillus sakei Probio-65 for the prevention of canine atopic dermatitis. J Microbiol Biotechnol 2015; 25:1966-1969. 36. Craig JM. Atopic dermatitis and the intestinal microbiota in humans and dogs. Vet Med Sci 2016. doi: 10.1002/vms3.24 37. Glos K, Linek M, Loewenstein C, et al. The efficacy of commercially available veterinary diets recommended for dogs with atopic dermatitis. Vet Dermatol 2008; 19:280-287. 38. Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007; 85:1185-1196.

The North American Veterinary Community (NAVC) and the Veterinary Innovation Council (VIC) are excited to announce the launch of their first ever Veterinary Innovation Awards. Sponsored by Zomedica, the awards provide anyone a chance to nominate passionate innovators and organizations that have dedicated themselves to the betterment of the animal health industry. The NAVC and VIC are honored to recognize those people and organizations that have made a difference in veterinary medicine and in the lives of animals everywhere. To learn more about the Veterinary Innovation Awards and to nominate an individual or organization visit VICAwards.com.

ACVN NUTRITION NOTES

39. Olivry T, Bizikova P. A systematic review of the evidence of reduced allergenicity and clinical benefit of food hydrolysates in dogs with cutaneous adverse food reactions. Vet Dermatol 2010; 21:32-41. 40. Willis-Mahn C, Remillard R, Tater K. ELISA testing for soy antigens in dry dog foods used in dietary elimination trials. JAAHA 2014; 50:383-389. 41. Raditic DM, Remillard RL, Tater KC. ELISA testing for common food antigens in four dry dog foods used in dietary elimination trials. J Anim Physiol Anim Nutr 2011; 95:90-97. 42. Harvey RG. Food allergy and dietary intolerance in dogs: a report of 25 cases. J Small Anim Pract 1993; 34:175-179. 43. Davis PJ, Smales CM, James DC. How can thermal processing modify the antigenicity of proteins? Allergy 2001; 56:56-60.

ACVN NUTRITION NOTES

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CONSIDER THIS CASE

An Uncontrolled Diabetic Dog Ann Della Maggiore, DVM, DACVIM University of California, Davis shutterstock.com/Jagodka

QUESTIONS: Investigating the Unstable Diabetic Dog

Buster, a 7-year-old male castrated beagle mix weighing 18 kg, was presented for evaluation of uncontrolled diabetes.

1. What are possible causes of poor diabetic control in this dog?

HISTORY

2. Are there problems with insulin handling and administration?

Previous Diagnosis

3. Is this dog receiving an appropriate insulin type and dose?

Six months before presentation, Buster was presented to his primary veterinarian for polyuria, polydipsia, and weight loss. Physical examination and complete blood count (CBC) were unremarkable, while the serum biochemical profile (Table 1) demonstrated:

4. What and when is the dog being fed, and does the dog receive any additional treats or table scraps? 5. What are possible causes of insulin resistance in this dog? 6. What additional diagnostics would help in better assessing diabetic control? Turn to page 52 for the answers to these questions.

TABLE 1 Buster: Historical Serum Biochemical Profile Results VARIABLE

RESULT

REFERENCE RANGE

Alkaline phosphatase (IU/L)

860

14–91

Cholesterol (mg/dL)

360

139–353

Glucose (mg/dL)

538

86–118

• Mildly increased alkaline phosphatase (ALP) • Mild hypercholesterolemia • Hyperglycemia The urinalysis showed glucosuria, with no evidence of ketones, white blood cells, or bacteria. Based on these findings, Buster was diagnosed with diabetes mellitus.

Medical Therapy After diagnosis, Buster’s primary veterinarian initiated therapy with neutral protamine Hagedorn (NPH) insulin at 9 U (0.5 U/kg) SC q12h. Intermittent spot MARCH/APRIL 2017

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blood glucose monitoring was used to determine adjustments in insulin dose and, based on variably high results (>350 mg/dL), Buster’s insulin dose was increased approximately every 3 days.

NPH insulin q12h. The insulin was from a new prescription, stored in the refrigerator, and the administration technique (visualized as part of history collection) appeared appropriate.

Upon presentation for a second opinion on diabetic control, Buster was receiving 30 U of

Buster had no other known medical conditions and was not receiving any other drugs or supplements.

Diet & Exercise Unstable Diabetic Dog: History & Physical Examination Evaluating a poorly controlled diabetic animal can be frustrating for both the clinician and the owner. A thorough history is key, including investigation into both the animal’s general history and specific questions related to diabetic history, such as initial diagnosis and management. When possible, available medical records should also be thoroughly reviewed. Key points to any diabetic animal’s history include the following1,2:

Diabetic diagnosis

• Confirmation of how initial diagnosis

was made • Previous insulin types used,

Insulin therapy

Monitoring

including doses, and animal’s response to each change in type and/or dose • Insulin syringes used and insulin storage • Insulin administration, including technique, frequency, and site of administration • Types and frequency of previous

monitoring techniques • Evidence of concurrent disease (eg,

Other medical history

vomiting, diarrhea, pain, alopecia) • Types and timing of medications/

supplements

Buster was receiving a maintenance diet (daily requirements calculated at 700 calories/day; he was receiving approximately 800 calories/ day), divided and fed in equal amounts roughly 10 to 12 hours apart. The diet and exercise pattern had been consistent since diagnosis.

CLINICAL SIGNS The owners noted that Buster was polyphagic, polyuric, and polydipsic, with no obvious improvement since initiation of insulin therapy. Buster had no recent vomiting, diarrhea, or alterations in appetite.

PHYSICAL EXAMINATION Physical examination revealed a symmetrically muscled dog with mild muscle atrophy, with a body condition score of 7/9. Buster had moderate periodontal disease, a grade III/VI left apical systolic heart murmur, incomplete bilateral diabetic cataracts, and a tense, nonpainful abdomen on palpation. No additional abnormalities were appreciated. TABLE 2 Buster: Serum Biochemical Profile & Urinalysis Abnormalities at Presentation VARIABLE

• Diet fed and feeding time, quantity,

Diet & exercise

and frequency • Additional food items (treats, supplemental food, bones, chew toys) and timing of administration • E xercise time, duration, and frequency; time of day is important in terms of how it correlates with insulin administration, meals, and blood glucose concentrations

A thorough physical examination is necessary to evaluate for concurrent related and unrelated disease processes.

RESULT

REFERENCE RANGE

21–72

Alkaline phosphatase (IU/L)

444

14–91

Cholesterol (mg/dL)

608

139–353

Blood glucose (mg/dL)

519

86–118

Glucosuria

Pyuria

Alanine aminotransferase (IU/L)

Urine specific gravity

CONSIDER THIS CASE

1.015

CONSIDER THIS CASE

DIAGNOSTIC APPROACH

Glucose Monitoring & Curves

Buster’s problem list of conditions—both related and unrelated to his diabetes mellitus—included:

The patient was hospitalized in order to better assess diabetic control through serial blood glucose curves and monitoring.

• Poorly controlled diabetes mellitus • Bilateral incomplete diabetic cataracts

Day 1: Blood glucose was assessed inhospital on the night of admission (Table 3), before insulin administration.

• Grade III/VI systolic heart murmur • Periodontal disease Suspected causes of poor diabetic control included:

• Insulin overdose • Inappropriate insulin type (eg, short duration of action) • Insulin resistance caused by concurrent disease

Initial Laboratory Analysis Routine CBC, serum biochemical profile, and urinalysis with urine culture were performed. The CBC was unremarkable and urine culture was negative for bacterial growth. The primary abnormalities noted on the serum biochemical profile were elevated ALP, hypercholesterolemia, and hyperglycemia (Table 2).

TABLE 3 Buster: Blood Glucose Measurements (mg/dL) During Hospitalization TIME

DAY 1: NPH 30 U

8 am

DAY 2: NPH 25 U

DAY 3: NPH 10 U

252

328

Meal fed; then insulin administered

Meal/ insulin

Day 2: Blood glucose monitoring began the next morning (Table 3). Because blood glucose was lower than anticipated at 8 am, Buster received 25 U of NPH insulin SC after a complete meal, with blood glucose measurements taken 2 hours later and then q2h.

Buster significantly responded to insulin while in the hospital, with a relatively low blood glucose at 8 pm. Buster was fed and no additional insulin was administered on Day 2. Blood glucose monitoring continued overnight until blood glucose was >200 mg/dL. Day 3: Buster received 10 U of NPH insulin SC after a complete meal in the morning, with response monitored throughout the day (Table 3).

Figure 1 depicts the blood glucose measurement trends revealed over the 3 days of in-hospital monitoring.

Unstable Diabetic Dog: Diagnostic Approach

10 am

107

394

12 pm

148

256

2 pm

169

227

4 pm

129

246

In addition, determine the suspected causes of poor diabetic control, which may include:

6 pm

129

217

• Problems with owner administration

528

132

251

• Activity of the insulin

Meal fed; then insulin administered

Meal fed; NO insulin administered

8 pm Meal/ insulin 10 pm

For a patient with uncontrolled diabetes mellitus, the goal of the diagnostic evaluation is to establish a problem list of conditions related and unrelated to the animal’s diabetes mellitus.

• Insulin overdose or underdose • Prolonged or short duration of insulin effect • Concurrent disease causing insulin resistance

245

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PEER REVIEWED

DIAGNOSIS & THERAPY On the basis of serial blood glucose curves and monitoring in the hospital, it was suspected that Buster was exhibiting clinical signs consistent with poor control caused by rebound hyperglycemia, also known as the Somogyi response.

FIGURE 1. Depiction of blood glucose measurements from 3 days of monitoring (Table 3). Yellow arrows denote time of insulin administration.

Blood Glucose Curves Blood glucose concentrations can vary significantly in diabetic animals. Blood glucose curves can, therefore, provide more useful impressions of how diabetic animals respond to insulin administration than single measurements alone. Concurrent monitoring of body weight, clinical signs (water consumption, urination, appetite), and fructosamine measurements should accompany blood glucose monitoring, as blood glucose curves are best evaluated with this additional information in hand. Key questions to ask when evaluating blood glucose curves include: 1. Is the insulin effective at decreasing the blood glucose? If ineffective, consider insulin underdose, overdose causing rebound hyperglycemia or Somogyi response, or insulin resistance. It is also important to review the animal’s history and physical examination findings to help prioritize possible causes of poor diabetic control. 2. What is the nadir? If the nadir is too high or too low, consider an insulin dose that alternates. 3. What is the duration of action of the insulin? If too short or too long, consider changing the insulin type. Clinicians must recognize the variability between blood glucose curves performed at home and those obtained in the hospital setting. Many owners may alter a pet’s daily routine (eg, feeding schedule, exercise) to accommodate the hospital visit. In addition, pets exhibiting fear or stress in a hospital setting are unlikely to be good candidates for in-hospital blood glucose curves. At-home blood glucose monitoring or other approaches (for example, continuous glucose monitors) must be considered.

CONSIDER THIS CASE

This diagnosis was based on Buster’s clinical response (reduced clinical signs and increased body weight) and improved blood glucose values, both of which were associated with a significant reduction in insulin dose. See The Somogyi Response, page 51, for further details on diagnosis of rebound hyperglycemia.

Challenges in Diagnosis The specific criteria for a Somogyi response (page 51) were not demonstrated on Buster’s blood glucose curves performed in the hospital. However, these criteria can be challenging to identify in hospital, and may not be identified at all because of:

• Infrequent sampling in the hospital • The fact that diabetogenic hormones released during the response can have lingering effects—up to 24 to 72 hours following the period of hypoglycemia • Increased stress caused by hospitalization According to the blood glucose values obtained in hospital for Buster, once the insulin dose was reduced significantly, Buster’s blood glucose values improved, leading to suspicion of insulin overdose.

Definitive Diagnosis In this dog, if the previous high insulin dose had been administered repeatedly, a Somogyi response with rebound hyperglycemia may have been documented in subsequent blood glucose curves.

Treatment & Follow-up Buster’s Day 3 dosage of NPH insulin (10 U SC q12h) was continued for 7 to 10 days, with a plan for the owner to return with Buster in 1 week for a blood glucose curve.

NOT ALL FLEA AND TICK CHEWS ARE CREATED EQUAL

Flea and tick protection that goes on and on and on...all month long

Introducing Simparica Monthly chewables for dogs that offer persistent protection from ﬂeas and ticks. Simparica acts fast—it starts killing ﬂeas within 3 hours and ticks within 8 hours1 —and keeps going strong for 35 days2 without losing effectiveness at the end of the month. IMPORTANT SAFETY INFORMATION: Simparica is for use only in dogs, 6 months of age and older. Simparica may cause abnormal neurologic signs such as tremors, decreased conscious proprioception, ataxia, decreased or absent menace, and/or seizures. Simparica has not been evaluated in dogs that are pregnant, breeding or lactating. Simparica has been safely used in dogs treated with commonly prescribed vaccines, parasiticides and other medications. The most frequently reported adverse reactions were vomiting and diarrhea. See full Prescribing Information on the back of this page and at www.zoetisUS.com/SimparicaPI.

Fetch more information about Simparica from Zoetis Customer Service at 1-888-ZOETIS-1 or 1-888-963-8471.

References: 1. Six RH, Geurden T, Carter L, et al. Evaluation of the speed of kill of sarolaner (Simparica™) against induced infestations of three species of ticks (Amblyomma maculatum, Ixodes scapularis, Ixodes ricinus) on dogs. Vet Parasitol. 2016;222:37-42. 2. Six RH, Everett WR, Young DR, et al. Efﬁcacy of a novel oral formulation of sarolaner (Simparica™) against ﬁve common tick species infesting dogs in the United States. Vet Parasitol. 2016;222:28-32. All trademarks are the property of Zoetis Services LLC or a related company or a licensor unless otherwise noted. © 2016 Zoetis Services LLC. All rights reserved. October 2016. SMP-00048

(sarolaner) Chewables FOR ORAL USE IN DOGS ONLY CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Description: SIMPARICA is a flavored, chewable tablet for administration to dogs over 6 months of age according to their weight. Each tablet is formulated to provide a minimum sarolaner dosage of 0.91 mg/lb (2 mg/kg) body weight. Sarolaner is a member of the isoxazoline class of parasiticides and the chemical name is 1-(5’-((5S)-5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)3’-H-spiro(azetidine-3,1’-(2)benzofuran)-1-yl)-2-(methylsulfonyl)ethanone. SIMPARICA contains the S-enantiomer of sarolaner. The chemical structure of the S-enantiomer of sarolaner is: Indications: SIMPARICA kills adult fleas, and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis), and the treatment and control of tick infestations [Amblyomma americanum (Lone Star tick), Amblyomma maculatum (Gulf Coast tick), Dermacentor variabilis (American dog tick), and Rhipicephalus sanguineus (brown dog tick)] for one month in dogs 6 months of age or older and weighing 2.8 pounds or more. Dosage and Administration: SIMPARICA is given orally once a month at the recommended minimum dosage of 0.91 mg/lb (2 mg/kg). Dosage Schedule: F

Body Weight 2.8 to 5.5 lbs 5.6 to 11.0 lbs 11.1 to 22.0 lbs 22.1 to 44.0 lbs 44.1 to 88.0 lbs 88.1 to 132.0 lbs >132.1 lbs

SAROLANER per Tablet (mg) Number of Tablets Administered 5 One 10 One 20 One 40 One 80 One 120 One Administer the appropriate combination of tablets

SIMPARICA can be offered by hand, in the food, or administered like other tablet medications. Care should be taken that the dog consumes the complete dose, and treated animals should be observed for a few minutes to ensure that part of the dose is not lost or refused. If a dose is missed, administer SIMPARICA and resume a monthly dosing schedule. SIMPARICA should be administered at monthly intervals. Flea Treatment and Prevention: Treatment with SIMPARICA may begin at any time of the year. In areas where fleas are common year-round, monthly treatment with SIMPARICA can continue the entire year without interruption. To minimize the likelihood of flea re-infestation, it is important to treat all dogs and cats within a household with an approved flea control product. Tick Treatment and Control: Treatment with SIMPARICA can begin at any time of the year (see Effectiveness). Contraindications: There are no known contraindications for the use of SIMPARICA. Warnings: Not for use in humans. Keep this and all drugs out of reach of children and pets. For use in dogs only. Do not use SIMPARICA in cats. SIMPARICA should not be used in dogs less than 6 months of age (see Animal Safety). Precautions: SIMPARICA may cause abnormal neurologic signs such as tremors, decreased conscious proprioception, ataxia, decreased or absent menace, and/or seizures (see Animal Safety). The safe use of SIMPARICA has not been evaluated in breeding, pregnant, or lactating dogs. Adverse Reactions: SIMPARICA was administered in a well-controlled US field study, which included a total of 479 dogs (315 dogs treated with SIMPARICA and 164 dogs treated with active control once monthly for three treatments). Over the 90-day study period, all observations of potential adverse reactions were recorded. Table 1. Dogs with adverse reactions Adverse reaction

sarolaner N

Vomiting Diarrhea Lethargy Inappetence

3 2 1 0

sarolaner % (n = 315) 0.95% 0.63% 0.32% 0%

active control N 9 2 2 3

active control % (n =164) 5.50% 1.20% 1.20% 1.80%

Additionally, one female dog aged 8.6 years exhibited lethargy, ataxia while posturing to eliminate, elevated third eyelids, and inappetence one day after receiving SIMPARICA concurrently with a heartworm preventative (ivermectin/pyrantel pamoate). The signs resolved one day later. After the day 14 visit, the owner elected to withdraw the dog from the study.

For a copy of the Safety Data Sheet (SDS) or to report adverse reactions call Zoetis Inc. at 1-888-963-8471. Additional information can be found at www.SIMPARICA.com. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or http://www.fda.gov/AnimalVeterinary/SafetyHealth. Clinical Pharmacology: Sarolaner is rapidly and well absorbed following oral administration of SIMPARICA. In a study of 12 Beagle dogs the mean maximum plasma concentration (Cmax) was 1100 ng/mL and the mean time to maximum concentration (Tmax) occurred at 3 hours following a single oral dose of 2 mg/kg to fasted animals. The mean oral bioavailability was 86% and 107% in fasted and fed dogs, respectively. The mean oral T1/2 values for fasted and fed animals was 10 and 12 days respectively. Sarolaner is distributed widely; the mean volume of distribution (Vdss) was 2.81 L/kg bodyweight following a 2 mg/kg intravenous dose of sarolaner. Sarolaner is highly bound (≥99.9%) to plasma proteins. The metabolism of sarolaner appears to be minimal in the dog. The primary route of sarolaner elimination from dogs is biliary excretion with elimination via the feces. Following repeat administration of SIMPARICA once every 28 days for 10 doses to Beagle dogs at 1X, 3X, and 5X the maximum intended clinical dose of 4 mg/kg, steady-state plasma concentrations were reached after the 6th dose. Following treatment at 1X, 3X, and 5X the maximum intended clinical dose of 4 mg/kg, sarolaner systemic exposure was dose proportional over the range 1X to 5X. Mode of Action: The active substance of SIMPARICA, sarolaner, is an acaricide and insecticide belonging to the isoxazoline group. Sarolaner inhibits the function of the neurotransmitter gamma aminobutyric acid (GABA) receptor and glutamate receptor, and works at the neuromuscular junction in insects. This results in uncontrolled neuromuscular activity leading to death in insects or acarines. Effectiveness: In a well-controlled laboratory study, SIMPARICA began to kill fleas 3 hours after initial administration and reduced the number of live fleas by ≥96.2% within 8 hours after flea infestation through Day 35. In a separate well-controlled laboratory study, SIMPARICA demonstrated 100% effectiveness against adult fleas within 24 hours following treatment and maintained 100% effectiveness against weekly re-infestations for 35 days. In a study to explore flea egg production and viability, SIMPARICA killed fleas before they could lay eggs for 35 days. In a study to simulate a flea-infested home environment, with flea infestations established prior to the start of treatment and re-infestations on Days 7, 37 and 67, SIMPARICA administered monthly for three months demonstrated >95.6% reduction in adult fleas within 14 days after treatment and reached 100% on Day 60. In well-controlled laboratory studies, SIMPARICA demonstrated ≥99% effectiveness against an initial infestation of Amblyomma americanum, Amblyomma maculatum, Dermacentor variabilis, and Rhipicephalus sanguineus 48 hours post-administration and maintained >96% effectiveness 48 hours post re-infestation for 30 days. In a well-controlled 90-day US field study conducted in households with existing flea infestations of varying severity, the effectiveness of SIMPARICA against fleas on Day 30, 60 and 90 visits compared to baseline was 99.4%, 99.8%, and 100%, respectively. Dogs with signs of flea allergy dermatitis showed improvement in erythema, papules, scaling, alopecia, dermatitis/pyodermatitis and pruritus as a direct result of eliminating fleas. Animal Safety: In a margin of safety study, SIMPARICA was administered orally to 8-week-old Beagle puppies at doses of 0, 1X, 3X, and 5X the maximum recommended dose (4 mg/kg) at 28-day intervals for 10 doses (8 dogs per group). The control group received placebo tablets. No neurologic signs were observed in the 1X group. In the 3X group, one male dog exhibited tremors and ataxia post-dose on Day 0; one female dog exhibited tremors on Days 1, 2, 3, and 5; and one female dog exhibited tremors on Day 1. In the 5X group, one female dog had a seizure on Day 61 (5 days after third dose); one female dog had tremors post-dose on Day 0 and abnormal head coordination after dosing on Day 140; and one female dog exhibited seizures associated with the second and fourth doses and tremors associated with the second and third doses. All dogs recovered without treatment. Except for the observation of abnormal head coordination in one dog in the 5X group two hours after dosing on Day 140 (dose 6). There were no treatment-related neurological signs observed once the dogs reached the age of 6 months. In a separate exploratory pharmacokinetic study, one female dog dosed at 12 mg/kg (3X the maximum recommended dose) exhibited lethargy, anorexia, and multiple neurological signs including ataxia, tremors, disorientation, hypersalivation, diminished proprioception, and absent menace, approximately 2 days after a third monthly dose. The dog was not treated, and was ultimately euthanized. The first two doses resulted in plasma concentrations that were consistent with those of the other dogs in the treatment group. Starting at 7 hours after the third dose, there was a rapid 2.5 fold increase in plasma concentrations within 41 hours, resulting in a Cmax more than 7-fold higher than the mean Cmax at the maximum recommended use dose. No cause for the sudden increase in sarolaner plasma concentrations was identified. Storage Information: Store at or below 30°C (86°F) with excursions permitted up to 40°C (104°F). How Supplied: SIMPARICA (sarolaner) Chewables are available in six flavored tablet sizes: 5, 10, 20, 40, 80, and 120 mg. Each tablet size is available in color-coded packages of one, three, or six tablets. NADA #141-452, Approved by FDA

Distributed by: Zoetis Inc. Kalamazoo, MI 49007 Made in Switzerland December 2015

30491300A&P

CONSIDER THIS CASE

At Buster’s follow-up appointment, his clinical signs had improved but not resolved. A blood glucose curve was performed, revealing a nadir of 260 mg/dL at 4 pm. The insulin was effective, but the nadir was not ideal. Thus, the dose was increased to 12 U of NPH insulin SC q12h. Additional follow-up showed that, with this dose, Buster’s clinical signs had resolved and his condition was controlled.

IN SUMMARY Unstable diabetic animals can be a struggle to manage in clinical practice. Thorough communication with the owner and examination of the animal, along with careful monitoring, are the key to successfully stabilizing these animals. Making small, infrequent insulin dose changes and allowing time to assess the animal’s response are the best ways to prevent insulin overdose.

The Somogyi Response The Somogyi response, also called rebound hyperglycemia and insulin-induced hyperglycemia, is the physiologic response to impending hypoglycemia. This response is characterized by stimulation of hepatic gluconeogenesis and secretion of diabetogenic hormones, including catecholamines and glucagon. Incidence & Risk Factors Limited literature supports the documentation of the Somogyi response in dogs and cats. A recent study suggests that, in cats receiving long-acting insulin analogs (eg, insulin glargine, insulin detemir), the Somogyi response is less common than initially suspected. 3 Factors that may increase risk for the Somogyi response in dogs and cats include: • I nsulin adjustments made very frequently, which does not give the patient time to equilibrate between doses • Insulin adjustments made in large increments • Lente insulin therapy q12h. Clinical Signs Clinical signs of hypoglycemia are often subtle and overshadowed by signs of hyperglycemia that go unnoticed by the client.1,2,4 Table 4 provides a list of common clinical signs of hyperglycemia and hypoglycemia. Diagnosis Diagnosis of the Somogyi response requires documentation of hypoglycemia (glucose <65 mg/dL) followed by hyperglycemia (glucose >300 mg/dL) after insulin administration.

TABLE 4 Common Clinical Signs of Hyperglycemia & Hypoglycemia in Dogs HYPERGLYCEMIA

HYPOGLYCEMIA

• Polydipsia • Polyphagia • Polyuria • Weight loss despite a good appetite

• A bnormal behavior or mentation changes • Collapse • Polyphagia • Tremors, seizures • Weakness, lethargy

Rebound hyperglycemia is often between 400 and 800mg/dL. It is suspected that patients exhibit sustained hyperglycemia and insulin resistance (up to 24–72 H) after a hypoglycemic event.1,2,4 The Somogyi response should be suspected when: • B lood glucose rapidly drops regardless of nadir. • D uration of insulin is greater than 12 hours. •T he patient is receiving a high dose of insulin (>1.5 U/kg). •T here is a cyclic history of good glycemic control for 1 to 2 days, followed by poor glycemic control for several days. •T he patient has gained weight despite suboptimal diabetic control. •T he patient has failed to improve despite increasing the insulin dose. Challenges with Recognition Several challenges surround diagnosis of a Somogyi response. The Somogyi response: • I s rare in dogs and cats. Previously believed to be more common in cats on lente insulins. Perceived to be less common in feline patients receiving new analog insulin preparations, although there is limited literature describing prevalence in diabetic animals.1,2,4 •D oes not happen in every episode of hypoglycemia. Reasons for this are unclear, but may include lack of a counterregulatory hormone response and duration of hypoglycemia. •C an be challenging to detect with blood glucose curves because the period of hypoglycemia can be very short and easily missed. • I s associated with unpredictable serum fructosamine measurements. Usually, a concentration greater than 500 mcmol/L confirms poor diabetic control.1,2,4 Because of these challenges, when insulin overdose is suspected, but not documented on a blood glucose curve, consider reducing the insulin dose. Once the dose has been reduced, instruct the owner to carefully monitor clinical signs for any subtle change and repeat monitoring at least 4 to 7 days after reducing the insulin dose.1,2,4

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PEER REVIEWED

Ann Della Maggiore

Ann Della Maggiore, DVM, DACVIM, serves as an assistant professor of clinical internal medicine at the University of California, Davis School of Veterinary Medicine, with a specific interest in small animal endocrinology. She received her veterinary degree from UC Davis, then completed a residency in small animal internal medicine at the same institution.

Caution Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Indications SENTINEL® SPECTRUM® (milbemycin oxime/lufenuron/praziquantel) is indicated for the prevention of heartworm disease caused by Dirofilaria immitis; for the prevention and control of flea populations (Ctenocephalides felis); and for the treatment and control of adult roundworm (Toxocara canis, Toxascaris leonina), adult hookworm (Ancylostoma caninum), adult whipworm (Trichuris vulpis), and adult tapeworm (Taenia pisiformis, Echinococcus multilocularis and Echinococcus granulosus) infections in dogs and puppies two pounds of body weight or greater and six weeks of age and older. Dosage and Administration SENTINEL SPECTRUM should be administered orally, once every month, at the minimum dosage of 0.23 mg/lb (0.5 mg/kg) milbemycin oxime, 4.55 mg/lb (10 mg/kg) lufenuron, and 2.28 mg/lb (5 mg/kg) praziquantel. For heartworm prevention, give once monthly for at least 6 months after exposure to mosquitoes.

Dosage Schedule

References

Praziquantel per Number of chewable chewables

Milbemycin Oxime per chewable

Lufenuron per chewable

2 to 8 lbs.

2.3 mg

46 mg

22.8 mg

One

8.1 to 25 lbs.

5.75 mg

115 mg

57 mg

One

25.1 to 50 lbs.

11.5 mg

230 mg

114 mg

One

50.1 to 100 lbs.

3. Roomp K, Rand J. Rebound hyperglycemia in diabetic cats. J Fel Med Surg 2016; 18(8):587-596.

23.0 mg

460 mg

228 mg

One

4. Nelson RW, Feldman EC. Canine diabetes mellitus. In Bonagura JD (ed). Kirk’s Current Veterinary Therapy (CVT) XIV, 14th ed. St. Louis: Elsevier, 1999, pp 244-245.

Body Weight

Over 100 lbs.

Rucinsky R, Cook A, Haley S, et al. AAHA diabetes management guidelines for dogs and cats. JAAHA 2010; 46(3):215-224.

2. Nelson R. Canine diabetes mellitus. In Feldman EC, Nelson RW, Reusch CE, et al (eds): Canine and Feline Endocrinology, 4th ed. St. Louis: Saunders, 2015, pp 213-257.

Administer the appropriate combination of chewables

To ensure adequate absorption, always administer SENTINEL SPECTRUM to dogs immediately after or in conjunction with a normal meal. SENTINEL SPECTRUM may be offered to the dog by hand or added to a small amount of dog food. The chewables should be administered in a manner that encourages the dog to chew, rather than to swallow without chewing. Chewables may be broken into pieces and fed to dogs that normally swallow treats whole. Care should be taken that the dog consumes the complete dose, and treated animals should be observed a few minutes after administration to ensure that no part of the dose is lost or rejected. If it is suspected that any of the dose has been lost, redosing is recommended.

ANSWERS: Investigating the Unstable Diabetic Dog 1. What are possible causes of poor diabetic control in this dog? Insulin overdose, inappropriate insulin type, insulin resistance caused by concurrent disease.

Contraindications There are no known contraindications to the use of SENTINEL SPECTRUM. Warnings Not for use in humans. Keep this and all drugs out of the reach of children. Precautions Treatment with fewer than 6 monthly doses after the last exposure to mosquitoes may not provide complete heartworm prevention.

2. Are there problems with insulin handling and administration? Not in this case.

Prior to administration of SENTINEL SPECTRUM, dogs should be tested for existing heartworm infections. At the discretion of the veterinarian, infected dogs should be treated to remove adult heartworms. SENTINEL SPECTRUM is not effective against adult D. immitis.

3. I s this dog receiving an appropriate insulin type and dose? Insulin dose is too high and does not provide good diabetic control; the insulin type should be appropriate, but duration of action cannot be assessed currently.

Mild, transient hypersensitivity reactions, such as labored breathing, vomiting, hypersalivation, and lethargy, have been noted in some dogs treated with milbemycin oxime carrying a high number of circulating microfilariae. These reactions are presumably caused by release of protein from dead or dying microfilariae. Do not use in puppies less than six weeks of age. Do not use in dogs or puppies less than two pounds of body weight.

4. What and when is the dog being fed, and does the dog receive any additional treats or table scraps? Appropriate caloric intake is provided twice daily, with no treats or table scraps.

The safety of SENTINEL SPECTRUM has not been evaluated in dogs used for breeding or in lactating females. Studies have been performed with milbemycin oxime and lufenuron alone. Adverse Reactions The following adverse reactions have been reported in dogs after administration of milbemycin oxime, lufenuron, or praziquantel: vomiting, depression/lethargy, pruritus, urticaria, diarrhea, anorexia, skin congestion, ataxia, convulsions, salivation, and weakness.

5. What are possible causes of insulin resistance in this dog? Hyperadrenocorticism, hypertriglyceridemia, insulin antibodies, periodontal disease, or other concurrent disease.

To report suspected adverse drug events, contact Virbac at 1-800-338-3659 or the FDA at 1-888-FDA-VETS. Information for Owner or Person Treating Animal Echinococcus multilocularis and Echinococcus granulosus are tapeworms found in wild canids and domestic dogs. E. multilocularis and E. granulosus can infect humans and cause serious disease (alveolar hydatid disease and hydatid disease, respectively). Owners of dogs living in areas where E. multilocularis or E. granulosus are endemic should be instructed on how to minimize their risk of exposure to these parasites, as well as their dog’s risk of exposure. Although SENTINEL SPECTRUM was 100% effective in laboratory studies in dogs against E. multilocularis and E. granulosus, no studies have been conducted to show that the use of this product will decrease the incidence of alveolar hydatid disease or hydatid disease in humans. Because the prepatent period for E. multilocularis may be as short as 26 days, dogs treated at the labeled monthly intervals may become reinfected and shed eggs between treatments.

6. What additional diagnostics would help in better assessing diabetic control? Blood glucose curve (performed in hospital or at home), fructosamine concentration; further diagnostics can be based on findings and may include systemic evaluation for concurrent disease or continuous glucose monitoring, if available.

Manufactured for: Virbac AH, Inc. P.O. Box 162059, Ft. Worth, TX 76161 NADA #141-333, Approved by FDA © 2015 Virbac Corporation. All Rights Reserved. SENTINEL and SPECTRUM are registered trademarks of Virbac Corporation. 02/15

CONSIDER THIS CASE

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The coverage and convenience you need with the compliance you want.1 Broad-spectrum protection—fleas,* heartworm, whipworm, roundworm, hookworm,† and tapeworm. 99% acceptance rate2 —Available in a tasty, beef and bacon flavored chew dogs love. Powerful flea prevention—Uses lufenuron, a unique ingredient that prevents flea infestations. Easy year-round coverage—Prevent and control parasites with just 1 chew, every 30 days. Built for compliance1 —Enhanced compliance compared to combination flea/tick and heartworm prevention regimens.1‡ To order, contact your distributor or call your Virbac representative at 1-844-4-VIRBAC (1-844-484-7222). Dogs should be tested for heartworm prior to use. Mild hypersensitivity reactions have been noted in some dogs carrying a high number of circulating microfilariae. Treatment with fewer than 6 monthly doses after the last exposure to mosquitoes may not provide complete heartworm prevention. Please see full product label for more information, or visit www.virbacvet.com. References: 1. Data on file, Vetstreet Data Analytics. Virbac Corporation. 2. SENTINEL® SPECTRUM® (milbemycin oxime/ lufenuron/praziquantel) [Freedom of Information Summary]. Greensboro, NC: Novartis Animal Health; 2011. * Prevents flea eggs and maggot-like larvae from developing; does not treat adult fleas. † A. caninum. ‡ SENTINEL® Brand Products.

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February 3-7, 2018 (Exhibits 4-7) • Orlando, Florida Orange County Convention Center • South Concourse

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HEARTWORM HOTLINE

AHS HEARTWORM HOTLINE

Focus on Canine Heartworm Disease Molly D. Savadelis, Research Professional II, BS, PhD Candidate University of Georgia shutterstock.com/Paksongpob Kasempisaisin

The Heartworm Hotline column is presented in partnership between Todayâ&#x20AC;&#x2122;s Veterinary Practice and the American Heartworm Society (heartwormsociety.org). The goal of the column is to communicate practical and timely information on prevention, diagnosis, and treatment of heartworm disease, as well as highlight current topics related to heartworm research and findings in veterinary medicine.

Heartworm disease (HWD) is caused by the filarial nematode Dirofilaria immitis. This parasite has a necessary mosquito intermediate host and has been found in many different mammalian species, including cats, dogs, monkeys, marine mammals, and rodents. Wild and domestic canids are the most prevalent hosts infected with D. immitis and have the largest adult worm burden. Mature, sexually reproductive adults are located in the right heart chambers and the pulmonary and lobar arteries. These adults produce microfilariae in the circulating

bloodstream, available to be ingested by female mosquitoes during a blood meal. The ingested microfilariae develop into the infective third-stage larvae (L3) after several molts. These L3 migrate to the mosquito head and mouthparts where they are deposited in hemolymph onto mammalian skin during subsequent blood meals. After the deposited L3 enter the host through the mosquito bite wound, they molt to fourth-stage larvae (L4). The L4 then migrate through the tissues toward the heart. Usually by day 90 to 120 post-infection, all of the worms have reached the main pulmonary artery and are mature adults. All D. immitis parasite life stages contain the endosymbiont bacteria Wolbachia, which is necessary for successful larval development and sexual reproduction. The American Heartworm Society (AHS) recommends treating heartwormpositive dogs with doxycycline to reduce the concentration of Wolbachia present during adulticide treatment, thereby reducing the inflammatory immune response to the bacteria.

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HEARTWORM HOTLINE

Heartworm preventives target L3 and L4 using macrocyclic lactones (MLs) such as ivermectin, selamectin, milbemycin oxime, and moxidectin. Recently, suspected ML-resistant D. immitis isolates have been identified. With the emergence of potential ML resistance, additional drugs capable of targeting heartworms and preventing HWD and a better understanding of our current HWD treatments are necessary.

Overview of Selected Literature Carretón and colleagues examined cardiopulmonary biomarkers and renal parameters during canine adult heartworm treatment. The classic 2-injection melarsomine treatment and the AHS’s recommended 3-injection melarsomine treatment—with and without prednisone—were compared. The dogs receiving the AHSrecommended heartworm treatment protocol experienced fewer and less severe clinicopathologic abnormalities compared with those receiving the 2-injection protocol. McCall and colleagues evaluated the effect of doxycycline on canine heartworm microfilariae and adult worms. Doxycycline was administered at 10 mg/kg PO q12h for 30 days as recommended by the AHS during canine adulticide treatment. A reduction in concentration of microfilariae post-doxycycline treatment was observed. Additionally, doxycycline treatment appeared to alter the morphology and motility of live adult heartworms recovered approximately 1 year post-treatment. Doxycycline-treated microfilariae fed to mosquitoes developed into infective L3. These L3 were injected into naïve dogs. At both 7 and 10 months post-infection of all naïve dogs, no live or dead adult heartworms were recovered. The results of this study suggest that doxycycline may be a successful adjunctive treatment against the transmission of potential MLresistant heartworms. Chandrashekar and colleagues evaluated the efficacy of doxycycline and Advantage Multi (bayerdvm.com) on immature adult D. immitis. Doxycycline was administered at 10 mg/kg PO q12h for 30 days, and imidacloprid 10 mg/ kg + moxidectin 2.5 mg/kg was applied topically every 30 days. This treatment regimen was 100% effective against approximately 3.5- and 5-month-old immature adult heartworms in preventing the development of canine HWD. This treatment regimen can be used to prevent HWD in dogs that have not been administered heartworm prevention for 2 to 5 months. Bourguinat and colleagues identified and confirmed 2 separate D. immitis isolates of ML resistance. Using populations of ML-susceptible and ML-resistant worms, whole genome analysis identified 6 loci containing the greatest genetic variation. These loci may be used in developing a genetic test to differentiate between MLsusceptible and ML-resistant isolates.

AHS HEARTWORM HOTLINE

Veterinarians must keep up with the guidelines for treating canine HWD, as well as determine if a case is potentially resistant to MLs. The articles below will facilitate heartworm treatment and management decisions made by veterinarians.

Evaluation of cardiopulmonary biomarkers during classic adulticide treatment versus the American Heartworm Society recommended treatment protocol in dogs infected by Dirofilaria immitis Carretón E, Morchón R, Simón F, et al. Vet Parasitol 2014;206(1-2):55-59. During adulticide treatment of dogs with HWD, the death of adult worms may cause pulmonary thromboembolism, pulmonary inflammation, congestive heart failure, or renal disease. Cardiopulmonary biomarkers and renal parameters can be used to monitor these potential adulticide side effects. The aim of this study was to evaluate biomarkers during the classic 2-injection protocol and the AHS-recommended heartworm treatment protocol by measuring cardiac troponin I (cTnI), myoglobin, D-dimers, blood urea nitrogen (BUN), creatinine, and urine protein:creatinine (UPC). The biomarker cTnI is released during myocardial inflammation, ischemia, or necrosis. D-dimers have been used to evaluate the presence of microthrombi and thromboembolism. Renal function can be measured by BUN, creatinine, and UPC concentrations. Fourteen dogs with confirmed D. immitis antigen and microfilariae were used in this study. Dogs were randomly assigned to a treatment protocol group. Group 1 dogs (n=5) received 2 melarsomine injections 24 hours apart. Dogs in group 2 (n=5)

HEARTWORM HOTLINE

and group 3 (n=4) received monthly ivermectin at 6 mcg/kg and 4 weeks of doxycycline at 10 mg/kg PO q12h after diagnosis. Thereafter, dogs received melarsomine injections at 2.5 mg/kg on days 60, 90, and 91. Dogs in group 3 also received prednisone, per AHS guidelines, after the first and third melarsomine injection on days 60 and 91 (Table). Blood and urine samples were obtained on days 0, 7, and 14 after the first melarsomine injection, and 30 days after the last melarsomine injection.

STUDY RESULTS • Elevations of D-dimers were mild to moderate. • A higher prevalence of dogs presented with elevated D-dimers after receiving the classic treatment, although this was not statistically significant. • The highest mean D-dimer concentrations occurred in dogs receiving the classic treatment and in dogs receiving prednisone. • 30 days after the last melarsomine injection, only 20% of dogs in groups 2 and 3 had pathologic concentrations of D-dimer, whereas 60% of dogs in group 1 presented with mild to moderate elevations of D-dimers. • cTnI levels were mildly elevated and decreased to normal levels in all study dogs post-adulticide treatment. • Blood myoglobin levels were mildly elevated in group 1 dogs throughout treatment.

• BUN and creatinine concentrations were within normal ranges for all dogs throughout treatment. • Group 1 dogs’ UPC values did not significantly change post-treatment; mean values for UPC were less than the cutoff value for clinical diagnosis of proteinuria in all groups at all time points.

CONCLUSIONS In analyzing the biomarkers used throughout this study, fewer and less severe abnormalities were documented in the dogs receiving the AHS-recommended heartworm treatment protocol. Although a higher prevalence of dogs presented with elevated D-dimers after receiving the classic treatment (group 1) compared with groups 2 and 3, this was not statistically significant and must be interpreted in light of the small numbers of dogs in this study, and in respect to the timing of the final blood sample. This 30-day post-melarsomine blood sample was obtained on day 121 for groups 2 and 3, while group 1 was collected on day 32. These findings indicate that the current AHS-recommended canine HWD treatment may produce less severe side effects (ie, thromboembolism) compared with the classic adulticide treatment. Therefore, this study supports the use of the AHSrecommended adulticide treatment.

TABLE Heartworm Adulticide Treatment Protocols DRUG PROTOCOL

FINAL BLOOD AND URINE SAMPLE COLLECTION

Melarsomine 2.5 mg/kg IM q24h for 2 doses

Day 32

• I vermectin 6 mcg/kg every month • Doxycycline 10 mg/kg PO q12h for 4 weeks • M elarsomine 2.5 mg/kg IM on days 60, 90, and 91

Day 121

GROUP

NUMBER OF DOGS

Group 1

Group 2

Group 3

• • • •

I vermectin 6 mcg/kg every month Doxycycline 10 mg/kg PO q12h for 4 weeks Melarsomine 2.5 mg/kg IM on days 60, 90, and 91 Prednisone PO on days 60 and 91 —0 .5 mg/kg BID for the first week, SID for the second week, and every other day for 2 weeks

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Effects of doxycycline on heartworm embryogenesis, transmission, circulating microfilaria, and adult worms in microfilaremic dogs McCall JW, Kramer L, Genchi C, et al. Vet Parasitol 2014;206(1-2):5-13. With the emergence of ML resistance, there is a need for additional drugs capable of targeting multiple D. immitis life stages. The tetracycline doxycycline is prescribed during canine heartworm adulticidal treatment to reduce the concentration of the endosymbiont bacteria Wolbachia and the pathologic inflammatory response caused by the death of adult worms and subsequent release of Wolbachia. Doxycycline has been demonstrated to prevent embryogenesis and development of larval stages and even to slowly kill adults in several filarial species harboring Wolbachia. The aim of this study was to evaluate the development and infectivity of D. immitis microfilariae postdoxycycline treatment. The concentration of circulating microfilariae, antigenemia, and adult worm recovery were analyzed in this study. Five heartworm-positive, microfilaremic dogs were administered doxycycline 10 mg/kg PO q12h for 30 days as recommended by the AHS before adulticide heartworm treatment. The dogs did not receive treatment with melarsomine and were housed in a mosquito-proof area; therefore, they were protected from new exposure to D. immitis. Blood samples were obtained monthly for approximately 1 year to monitor heartworm antigen status and the concentration of microfilariae. Approximately every 2 to 3 months, mosquitoes were allowed to feed, ingesting blood with microfilariae that had the potential to develop into infective L3. The L3 were then injected into naïve dogs to monitor infectivity post-doxycycline treatment. Doxycycline-treated dogs were necropsied approximately 1 year post-treatment, and overall adult worm recovery and morphology were analyzed.

AHS HEARTWORM HOTLINE

STUDY RESULTS • Circulating microfilariae concentration in doxycycline-treated dogs dropped below the level of detection after approximately 164 days post-treatment. • Heartworm antigen was detected throughout the study in both control and doxycycline-treated dogs. • Dead and live adult worms were recovered from doxycycline-treated dogs. • Live adult worms recovered from doxycycline-treated dogs were abnormal in appearance and motility. • Live adult worms recovered from control dogs were normal in motility and appearance. • No heartworm antigen nor detectable circulating microfilariae were present in naïve dogs receiving L3 developed from microfilariae collected from dogs approximately 2.5 months after doxycycline therapy; no live or dead worms were recovered from these previously naïve dogs 10 months post-infection. • No heartworm antigen nor detectable circulating microfilariae were present in naïve dogs receiving L3 developed from microfilariae collected from doxycycline-treated dogs approximately 5 months post-treatment; no live or dead worms were recovered from these previously naïve dogs 7 months post-infection.

CONCLUSIONS The AHS’s recommended adulticide treatment for canine HWD uses the tetracycline doxycycline to reduce the concentration of Wolbachia present in all parasitic life stages. Successful sexual reproduction and development of parasitic larval stages are dependent on the presence of Wolbachia. This study demonstrated a reduction in concentration of circulating microfilariae post-doxycycline treatment, which could be attributed to an impairment of sexual reproduction of adult heartworms. The doxycycline therapy appeared to alter

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the morphology and motility of live adult heartworms recovered from infected dogs approximately 1 year after treatment. Doxycycline-treated microfilariae fed to mosquitoes developed infective L3, which were injected into naïve dogs. At both 7 and 10 months post-infection of all naïve dogs, no live or dead adult heartworms where recovered. This indicates L3 derived from doxycyclinetreated microfilariae lack the ability to successfully develop into adult heartworms. The dogs in this controlled study were kept in mosquito-proof housing, preventing coinfection with heartworms that had not previously been exposed to doxycycline. Despite the small number of dogs in each experimental group, the data collected is compelling that Wolbachia does indeed play an important role in the survival, development, and infectivity of heartworms. The results of this study suggest that doxycycline may be a successful adjunctive treatment against the propagation of potential ML-resistant heartworms. If a canine with ML-resistant HWD is treated using the AHS’s recommended treatment protocol, the use of doxycycline may prevent further transmission of resistant heartworms.

Experimental Dirofilaria immitis infection in dogs: Effects of doxycycline and Advantage Multi® administration on immature adult parasites Chandrashekar R, Beall MJ, Saucier J, et al. Vet Parasitol 2014;206(1-2):93-98. The MLs ivermectin, milbemycin oxime, moxidectin, and selamectin are used in the prevention of HWD by killing D. immitis L3 and L4, preventing the development of adult worms in the pulmonary artery. Many of these MLs have been tested for adulticidal effects.

AHS HEARTWORM HOTLINE

The aim of this study was to evaluate the efficacy of doxycycline and 10% imidacloprid + 2.5% moxidectin against immature adult heartworms in experimentally infected dogs. This study specifically investigated the effect of this treatment on the concentration of microfilariae circulating in the bloodstream, antigenemia, and adult worm recovery at necropsy. Twelve dogs were randomly assigned to 3 groups. Two dogs in each group were infected with 6 D. immitis L3, and 2 dogs from each group were infected with 12 D. immitis L3. These low numbers of L3 more closely resemble a natural infection occurring over a period of time. The treatment regimen of 30 days of doxycycline 10 mg/kg PO q12h and imidacloprid 10 mg/ kg + moxidectin 2.5 mg/kg topically every 30 days was initiated at study day 105 (3.5 months post-infection) for group A dogs and at study day 149 (5 months post-infection) for group B dogs. Necropsy for groups A, B, and C (untreated control) were performed on study day 407 (14 months post-infection). Blood and serum samples were collected every 2 to 4 weeks for quantification of microfilariae and detection of D. immitis antigen by the commercially available test kit PetChek PF HW Antigen Test (idexx.com).

STUDY RESULTS • No live nor dead adult worms were recovered from groups A and B. • Live adult worms were recovered from group C. • Microfilariae were not detected in any experimental group throughout the course of this study. Intermittent antigenemia was detected in groups A and B, but detectable antigenemia was not found in any treated dog by the end of the study. Group C dogs infected with 6 L3 did not have detectable antigenemia; however, those infected with 12 L3 had detectable antigenemia that persisted until the end of the study.

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As with all drugs, side effects may occur. In field studies the most common side effects reported were polyuria, polydipsia, depression/lethargy, inappropriate urination, alopecia, decreased appetite/anorexia, panting, vomiting, diarrhea, shaking/trembling, polyphagia, urinary tract infection, urinary tract incontinence and restlessness. ZYCORTAL Suspension should be used with caution in dogs with congestive heart disease, edema, severe renal disease or primary hepatic failure. Dogs presenting in Addisonian crisis must be rehydrated with appropriate intravenous therapy before starting treatment with ZYCORTAL suspension. Refer to the prescribing information for complete details or visit www.dechra-us.com. * Contact your distributor or Dechra rep for details on how to receive your free vial. Order must be placed on a single invoice. Limit 3 free bottles of injectable Synthetic ACTH per month, per account. Offers valid through June 30, 2016. NADA 141-444, Approved by FDA CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. Dechra Veterinary Products US and the Dechra D logo are registered trademarks of Dechra Pharmaceuticals PLC.

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HEARTWORM HOTLINE

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The treatment regimen of doxycycline 10 mg/kg PO q12h for 30 days and monthly topical administration of 10% imidacloprid + 2.5% moxidectin was 100% effective against immature adult heartworms in preventing canine HWD. While this study had 100% prevention of canine HWD development, there were small numbers of dogs in each experimental group, preventing any statistical analysis of these results.

Brief Summary (For Full Prescribing Information, see package insert) CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION: Desoxycorticosterone pivalate is a mineralocorticoid hormone. Zycortal Suspension contains 25mg/ml of desoxycorticosterone pivalate.

Immature adult worms would have been present primarily in the lobar arteries of these dogs when treatment was initiated. No live or dead worms were recovered at necropsy of both treated groups. This may indicate that the treatment regimen successfully killed the parasites before they developed into sexually mature adults.

INDICATION: For use as replacement therapy for mineralocorticoid deficiency in dogs with primary hypoadrenocorticism (Addison’s disease). CONTRAINDICATIONS: Do not use ZYCORTAL Suspension in dogs that have previously had a hypersensitivity reaction to desoxycorticosterone pivalate.

In a study to be published in the near future, monthly topical administration of 10% imidacloprid + 2.5% moxidectin in combination with doxycycline 10 mg/kg PO q12h for 30 days has been evaluated against sexually mature adult heartworms. This treatment regimen resulted in the elimination of circulating microfilariae within 21 days post-treatment, and with continued topical therapy had a 95.9% efficacy in eliminating sexually mature adult heartworms after 10 months.1

WARNINGS: Use ZYCORTAL Suspension with caution in dogs with congestive heart disease, edema, severe renal disease or primary hepatic failure. Desoxycorticosterone pivalate may cause polyuria, polydipsia, increased blood volume, edema and cardiac enlargement. Excessive weight gain may indicate fluid retention secondary to sodium retention. HUMAN WARNINGS: Not for human use. Keep this and all drugs out of the reach of children. Consult a physician in case of accidental human exposure.

This treatment regimen can be used in veterinary practices in endemic and nonendemic areas for 2 different scenarios:

PRECAUTIONS: Any dog presenting with severe hypovolemia, dehydration, pre-renal azotemia and inadequate tissue perfusion (“Addisonian crisis”) must be rehydrated with intravenous fluid (saline) therapy before starting treatment with ZYCORTAL Suspension. The effectiveness of ZYCORTAL Suspension may be reduced if potassium-sparing diuretics, such as spironolactone, are administered concurrently.

• 2- to 5-month-old dogs • ≥6-month-old dogs that have missed 2 to 5 months of heartworm prevention Utilizing this treatment regimen against immature adult heartworms prevents the development of sexually mature adults, greatly reducing pathology associated with HWD, and eliminating transmission of microfilariae to other animals in the area. In addition, this treatment can be prescribed without having to wait 6 to 12 months after a period of noncompliance with heartworm preventives for adult heartworms to develop and become detectable by commercially available heartworm antigen tests.

ADVERSE REACTIONS: The field safety analysis included evaluation of 152 dogs. The most common adverse reactions reported are polyuria, polydipsia, depression/lethargy, inappropriate urination, alopecia, decreased appetite/anorexia, panting, vomiting, diarrhea, shaking/trembling, polyphagia, urinary tract infection, urinary tract incontinence and restlessness. Reports of anaphylaxis and anemia have been associated with a different desoxycorticosterone pivalate injectable suspension product.

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Molly D. Savadelis

Molly D. Savadelis is a PhD student at the University of Georgia in the Department of Infectious Diseases. Her dissertation work is focused on canine heartworm disease treatments utilizing the combination of macrocyclic lactones and tetracyclines and how these various treatments may affect heartworm diagnostics. She hopes to continue her career working on both canine and feline heartworm disease.

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AHS HEARTWORM HOTLINE

HEARTWORM HOTLINE

Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance Bourguinat C, Lee ACY, Lizundia R, et al. Vet Parasitol 2015;210(3-4):167-178. Lack of efficacy (LOE) claims for ML heartworm preventive products have increased in locations around the United States. Many of these cases can be attributed to improper administration of these products or inconsistent compliance. Despite this, some LOE claims are suspected ML resistance. Resistance to the ML ivermectin has recently been confirmed.2 Genetic markers that discriminate between susceptible and ML-resistant heartworm isolates have not been identified but may greatly facilitate testing to differentiate LOE claims. A genetic test based on molecular markers for ML-resistant phenotypes would facilitate identification and geographic mapping of MLresistant cases, as well as guide future research to produce effective alternative drugs. The aims of this study were to identify and confirm ML-resistant LOE cases, and then use the confirmed ML-resistant strains to search for loci within the genome associated with the resistant phenotype. Two LOE suspected ML-resistant cases, Td2008 from Louisiana and Jd2009 from Arkansas, were used in this study. Ten beagles were infected with Td2008 strain, and 12 beagles were infected with Jd2009 strain heartworm. Thirty days post-infection with Td2008 or Jd2009, the beagles were treated with commercially available chewable ivermectin tablets administered at 0.006 to 0.013 mg/kg PO monthly for 9 or 5 months, respectively. Necropsies were then performed to recover adult heartworms. Adult heartworm DNA from ML-susceptible populations and microfilarial DNA from ML-

resistant populations were pooled for whole genome analysis. The susceptible population comprised DNA samples from Missouri strain heartworm infected dogs (TRS Labs Inc, Athens, GA) and naturally infected dogs from Grand Canary Island, Spain, Grenada, and the Po Basin in Northern Italy.

STUDY RESULTS • Efficacy of ivermectin against the Td2008 strain was 23.8% after 9 months of treatment. • Efficacy of ivermectin against the Jd2009 strain was 71.3% after 5 months of treatment. • 186 loci were identified as potential molecular markers for ML resistance; 158 of these loci were statistically significantly different between susceptible and resistant populations. • Six loci were identified as the best potential genetic markers for differentiating between susceptible and resistant populations, because they contained the lowest frequency of the susceptible genotype in the LOE or resistant populations.

CONCLUSIONS This study confirms that the Louisiana Td2008 and Arkansas Jd2009 canine heartworm strains are indeed resistant to MLs. This was demonstrated by the development of adult heartworms despite 9 and 5 months of treatment with chewable ivermectin administered at 0.006 to 0.013 mg/kg PO for both strains. This study observed 6 specific loci within the genome of LOE and ML-resistant populations with the lowest frequency in susceptible genotypes. The 6 loci identified contain single nucleotide polymorphisms, representing genetic variation between susceptible populations and ML-resistant and LOE populations. While DNA was analyzed from several geographic locations for susceptible populations, these 6 loci were identified from polymorphic loci that showed no significant nucleotide difference attributable to geography between all the susceptible populations. MARCH/APRIL 2017

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The 6 loci identified in this study may be used to differentiate between ML-susceptible and ML-resistant populations, but they do not identify the exact mechanism of ML resistance. Despite this, the possibility of genetic testing capable of identifying ML-resistant heartworm isolates would allow geographic mapping and surveillance to help scientists better understand the spread of ML resistance. With this demonstrated ML resistance, it is necessary to develop a test capable of distinguishing between noncompliance and ML-resistant cases.

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The genetic markers characterized in this study may provide the starting point for the development of such testing. With this, LOE and suspected ML-resistant D. immitis cases should continue to be investigated and examined for additional genetic markers for ML resistance. References 1.

Savadelis MD, Dzimianski MT, Coleman A, et al. Assessment of parasitological and clinical findings in heartworm-infected beagles treated with Advantage Multi® and doxycycline. Presented at: AHS Triennial Symposium. 2016.

2. Pulaski CN, Malone JB, Bourguinat C, et al. Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs. Parasit Vectors 2014;7:494.

Sherrie O’Brien, DVM Passion for feline medicine

VetFolio User Since 2016

Getting Started “We as veterinarians are good at multitasking. I can cook dinner, fold laundry or work out on my exercise bike while I listen to a class. I can even listen to a podcast while I am driving to an alumni event. The education comes to you!”

Staying Fresh “Our profession is constantly changing, and VetFolio allows you to engage in this change. If you have recently graduated, there are surgery videos and classes on the subjects you may have not covered deeply in school. If you have been out of school for over five years, VetFolio can help you stay current and academically fresh. We are never too old to learn!”

Continuing the Experience “I use the information learned on VetFolio daily. There are a variety of topics that I incorporate into my daily discussions with clients, technicians and rescue groups. Whether it has to deal with the pros and cons of early spay/neuter or the life expectancy of a dog with splenic HSA, the classes offer information that can be used in real-life practice. VetFolio also allows one to stay medically current and have access to the newest products coming out on the market!”

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EAR DISEASE IN THE DOG AND CAT

PEER REVIEWED

SURGICAL APPROACH TO

External and Middle Ear Disease in the Dog and Cat Mark Cofone, VMD, DACVS Veterinary Specialty Center, Wilmington, Delaware

Diseases of the external and middle ear are common problems in dogs and cats. Chronic otitis externa alone accounts for approximately 10% of admissions to small animal hospitals.1 Ear disease often goes unnoticed by the owner until the disease has progressed, become well established, and led to irreversible structural changes. Initial medical management may fail for a variety of reasons. Diseases of the external ear canal and middle ear are often related to more than one underlying problem. For these reasons and others, surgery may become the most effective recourse for treatment (Table 1).

CAUSES OF OTITIS EXTERNA AND MEDIA • Hypersensitivity and allergic disorders: the two most common primary causes of otitis externa in dogs2

• Infection: usually secondary to other problems, but once established can be difficult to treat and lead to significant structural damage to the external canal and middle ear • Tumors: benign and malignant • Parasites • Foreign bodies • Conformation of the ear canal and pinna Infectious, parasitic, and immune or allergic causes of ear disease, if recognized early and treated appropriately, can be managed without surgery. If appropriate medical management fails to cure or control the primary disease process or if a tumor is present, surgery can be an effective adjunct or primary therapy (Figure 1).

DISEASES OF THE EAR are common problems in both the dog and cat. Chronic otitis externa alone accounts for approximately 10% of admissions to small animal hospitals.

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PRESURGICAL DIAGNOSTIC TESTING • Otoscopic exam: Evaluating the vertical and horizontal ear canals otoscopically or with video otoscopy is important in deciding whether surgery is indicated and which surgical procedure would be most beneficial to the patient. Evaluation of the eardrum in an ear that has had chronic otitis but appears to have a normal canal diameter may be difficult regardless of the presence of middle ear disease, especially if discharge is present in the canal. Dogs and cats that have had chronic ear disease are in pain and must be sedated or anesthetized. If it is obvious that the ear canal is stenotic, then performing this exam may not be necessary or even possible. • Neurologic exam: Neurologic deficits are not usually present in patients being evaluated for ear disease. If present, they must be documented because they may determine whether other diagnostic testing is performed and can limit the potential benefits of surgery. The most common neurologic deficits that may accompany ear disease are facial nerve paralysis, vestibular disease (peripheral or central), Horner’s syndrome, and deafness.3 If neurologic deficits are present, a more in-depth evaluation of the middle ear should be considered. This may include skull radiography; however, computed tomography (CT) and magnetic resonance imaging (MRI) are more sensitive in evaluating both bone and soft tissue changes of the bulla and middle ear. • Complete blood count/chemistry screen and thyroxine: Patients may have concurrent medical

problems that contribute to ear disease. Screening for Cushing’s disease and hypothyroidism is advisable before surgery on the ears.

• Skull radiography, CT, MRI: Skull radiography can be used to evaluate the tympanic bulla and external ear canals. The bulla can be evaluated for soft tissue or fluid opacities occupying the bulla, periosteal change, and bony lysis. The ear canals can be evaluated for patency and mineralization. Skull radiographs can be difficult to interpret because of superimposition of other bony structures.4 CT and MRI have become more available and are superior in evaluating the bulla and ear canals for changes related to both bone and soft tissue.5

SURGICAL OPTIONS FOR THE EXTERNAL AND MIDDLE EAR Lateral Ear Canal Resection C. P. Zepp first described lateral ear canal resection (LECR) in 1949, and this surgical procedure is still often called a “Zepp.”6 LECR is used to treat chronic otitis before the vertical and horizontal canals become stenotic. It can also be used in resecting benign tumors involving the lateral wall of the vertical canal. The procedure involves removing the lateral half of the vertical ear canal and creating a drainage board for the horizontal ear canal. This creates an ear canal in a dog or cat that more closely resembles that of a person. When performed correctly, it allows better access to the horizontal canal for application of medication and allows discharge in the horizontal canal to drain without traversing up the vertical canal. If significant

TABLE 1 Types of External and Middle Ear Surgery

SURGERY TYPE

INDICATIONS

Lateral ear canal resection

Chronic otitis externa and or media without stenosis of ear canal Benign tumors involving the lateral wall of the vertical canal

Total ear canal ablation

Chronic otitis externa with stenosis of ear canal Benign or malignant tumors involving the external ear canal

Lateral bulla osteotomy

Performed concurrently with total ear canal ablation to treat disease in the middle ear

Ventral bulla osteotomy

Used to treat disease confined to the middle ear or concurrently with total ear canal ablation

EAR DISEASE IN THE DOG AND CAT

Clients want to fight fleas and ticks – not their dogs. Protect dogs with the beefflavored chew they love.1

Data on file at Merial.

IMPORTANT SAFETY INFORMATION: NexGard® is for use in dogs only. The most frequently reported adverse reactions included pruritus, vomiting, dry/flaky skin, diarrhea, lethargy, and lack of appetite. The safe use of NexGard in pregnant, breeding, or lactating dogs has not been evaluated. Use with caution in dogs with a history of seizures. For more information, see full prescribing information or visit www.NexGardForDogs.com.

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middle ear disease is also present, this procedure can be combined with ventral bulla osteotomy (VBO) to treat both the external and middle ear. With a narrowed external ear canal, LECR will not provide adequate drainage and the patient will continue to exhibit clinical signs. It is important to consider LECR early in the treatment of otitis. When treating a malignant tumor involving the ear canal, LECR has been shown to have an inferior outcome compared with total ear canal ablation.4

CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Description: NexGard® (afoxolaner) is available in four sizes of beef-flavored, soft chewables for oral administration to dogs and puppies according to their weight. Each chewable is formulated to provide a minimum afoxolaner dosage of 1.14 mg/lb (2.5 mg/ kg). Afoxolaner has the chemical composition 1-Naphthalenecarboxamide, 4-[5- [3-chloro-5-(trifluoromethyl)-phenyl]-4, 5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl. Indications: NexGard kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis), and the treatment and control of Black-legged tick (Ixodes scapularis), American Dog tick (Dermacentor variabilis), Lone Star tick (Amblyomma americanum), and Brown dog tick (Rhipicephalus sanguineus) infestations in dogs and puppies 8 weeks of age and older, weighing 4 pounds of body weight or greater, for one month. Dosage and Administration: NexGard is given orally once a month, at the minimum dosage of 1.14 mg/lb (2.5 mg/kg). Dosing Schedule: Body Weight 4.0 to 10.0 lbs. 10.1 to 24.0 lbs. 24.1 to 60.0 lbs. 60.1 to 121.0 lbs. Over 121.0 lbs.

Afoxolaner Per Chewables Chewable (mg) Administered 11.3 One 28.3 One 68 One 136 One Administer the appropriate combination of chewables

NexGard can be administered with or without food. Care should be taken that the dog consumes the complete dose, and treated animals should be observed for a few minutes to ensure that part of the dose is not lost or refused. If it is suspected that any of the dose has been lost or if vomiting occurs within two hours of administration, redose with another full dose. If a dose is missed, administer NexGard and resume a monthly dosing schedule. Flea Treatment and Prevention: Treatment with NexGard may begin at any time of the year. In areas where fleas are common year-round, monthly treatment with NexGard should continue the entire year without interruption. To minimize the likelihood of flea reinfestation, it is important to treat all animals within a household with an approved flea control product. Tick Treatment and Control: Treatment with NexGard may begin at any time of the year (see Effectiveness). Contraindications: There are no known contraindications for the use of NexGard. Warnings: Not for use in humans. Keep this and all drugs out of the reach of children. In case of accidental ingestion, contact a physician immediately. Precautions: The safe use of NexGard in breeding, pregnant or lactating dogs has not been evaluated. Use with caution in dogs with a history of seizures (see Adverse Reactions). Adverse Reactions: In a well-controlled US field study, which included a total of 333 households and 615 treated dogs (415 administered afoxolaner; 200 administered active control), no serious adverse reactions were observed with NexGard. Over the 90-day study period, all observations of potential adverse reactions were recorded. The most frequent reactions reported at an incidence of > 1% within any of the three months of observations are presented in the following table. The most frequently reported adverse reaction was vomiting. The occurrence of vomiting was generally self-limiting and of short duration and tended to decrease with subsequent doses in both groups. Five treated dogs experienced anorexia during the study, and two of those dogs experienced anorexia with the first dose but not subsequent doses. Table 1: Dogs With Adverse Reactions. Treatment Group Afoxolaner

Vomiting (with and without blood) Dry/Flaky Skin Diarrhea (with and without blood) Lethargy Anorexia

N1 17 13 13 7 5

% (n=415) 4.1 3.1 3.1 1.7 1.2

Total Ear Canal Ablation Total ear canal ablation (TECA) is considered a salvage procedure and is used to treat end-stage otitis externa and malignant tumors of the ear canal. End-stage ear disease occurs when stenosis of the ear canal is present with inflammation and fibrosis that prevents drainage of otic discharge from the horizontal canal to and out of the vertical canal.7 Chronic tissue change makes it impossible to get topical medication to the entire diseased canal and for discharge to exit the canal. In these cases, the surfaces of the vertical and horizontal canals often have ulcerations, and the auricular cartilage can be mineralized. Dogs with end-stage ear disease can no longer be treated medically and cannot be adequately treated by LECR. TECA is also recommended for treating malignant tumors of the ear canal because of the better outcome when compared with LECR.

Oral active control

N2 25 2 7 4 9

% (n=200) 12.5 1.0 3.5 2.0 4.5

Number of dogs in the afoxolaner treatment group with the identified abnormality. 2 Number of dogs in the control group with the identified abnormality. In the US field study, one dog with a history of seizures experienced a seizure on the same day after receiving the first dose and on the same day after receiving the second dose of NexGard. This dog experienced a third seizure one week after receiving the third dose. The dog remained enrolled and completed the study. Another dog with a history of seizures had a seizure 19 days after the third dose of NexGard. The dog remained enrolled and completed the study. A third dog with a history of seizures received NexGard and experienced no seizures throughout the study. To report suspected adverse events, for technical assistance or to obtain a copy of the MSDS, contact Merial at 1-888-6374251 or www.merial.com/NexGard. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth. Mode of Action: Afoxolaner is a member of the isoxazoline family, shown to bind at a binding site to inhibit insect and acarine ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA), thereby blocking preand post-synaptic transfer of chloride ions across cell membranes. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of the central nervous system and death of insects and acarines. The selective toxicity of afoxolaner between insects and acarines and mammals may be inferred by the differential sensitivity of the insects and acarines’ GABA receptors versus mammalian GABA receptors. Effectiveness: In a well-controlled laboratory study, NexGard began to kill fleas four hours after initial administration and demonstrated >99% effectiveness at eight hours. In a separate well-controlled laboratory study, NexGard demonstrated 100% effectiveness against adult fleas 24 hours post-infestation for 35 days, and was ≥ 93% effective at 12 hours post-infestation through Day 21, and on Day 35. On Day 28, NexGard was 81.1% effective 12 hours post-infestation. Dogs in both the treated and control groups that were infested with fleas on Day -1 generated flea eggs at 12- and 24-hours post-treatment (0-11 eggs and 1-17 eggs in the NexGard treated dogs, and 4-90 eggs and 0-118 eggs in the control dogs, at 12- and 24-hours, respectively). At subsequent evaluations post-infestation, fleas from dogs in the treated group were essentially unable to produce any eggs (0-1 eggs) while fleas from dogs in the control group continued to produce eggs (1-141 eggs). In a 90-day US field study conducted in households with existing flea infestations of varying severity, the effectiveness of NexGard against fleas on the Day 30, 60 and 90 visits compared with baseline was 98.0%, 99.7%, and 99.9%, respectively. Collectively, the data from the three studies (two laboratory and one field) demonstrate that NexGard kills fleas before they can lay eggs, thus preventing subsequent flea infestations after the start of treatment of existing flea infestations. In well-controlled laboratory studies, NexGard demonstrated >97% effectiveness against Dermacentor variabilis, >94% effectiveness against Ixodes scapularis, and >93% effectiveness against Rhipicephalus sanguineus, 48 hours post-infestation for 30 days. At 72 hours post-infestation, NexGard demonstrated >97% effectiveness against Amblyomma americanum for 30 days. Animal Safety: In a margin of safety study, NexGard was administered orally to 8 to 9-week-old Beagle puppies at 1, 3, and 5 times the maximum exposure dose (6.3 mg/kg) for three treatments every 28 days, followed by three treatments every 14 days, for a total of six treatments. Dogs in the control group were sham-dosed. There were no clinically-relevant effects related to treatment on physical examination, body weight, food consumption, clinical pathology (hematology, clinical chemistries, or coagulation tests), gross pathology, histopathology or organ weights. Vomiting occurred throughout the study, with a similar incidence in the treated and control groups, including one dog in the 5x group that vomited four hours after treatment. In a well-controlled field study, NexGard was used concomitantly with other medications, such as vaccines, anthelmintics, antibiotics (including topicals), steroids, NSAIDS, anesthetics, and antihistamines. No adverse reactions were observed from the concomitant use of NexGard with other medications. Storage Information: Store at or below 30°C (86°F) with excursions permitted up to 40°C (104°F). How Supplied: NexGard is available in four sizes of beef-flavored soft chewables: 11.3, 28.3, 68 or 136 mg afoxolaner. Each chewable size is available in color-coded packages of 1, 3 or 6 beef-flavored chewables. 1

TECA involves removing the entire external ear canal and should in all cases be combined with a lateral bulla osteotomy (LBO) or VBO. Patients who undergo bilateral TECA combined with LBO are essentially deaf.8 The complication rate associated with TECA ranges from 21% to 82%, with the most common complication being facial nerve paralysis.3,7,9

Lateral Bulla Osteotomy LBO can be used in conjunction with TECA to treat disease within the middle ear. LBO allows access to the middle ear so that exudate and necrotic epithelium can be removed and the middle ear can be adequately flushed. During this procedure, it is important to remove enough of the lateral ventral wall of the bulla to access the middle ear with a small curette. The external carotid artery and maxillary

NADA 141-406, Approved by FDA Marketed by: Frontline Vet Labs™, a Division of Merial, Inc. Duluth, GA 30096-4640 USA Made in Brazil. ®NexGard is a registered trademark, and TMFRONTLINE VET LABS is a trademark, of Merial. ©2015 Merial. All rights reserved. 1050-4493-03 Rev. 1/2015

EAR DISEASE IN THE DOG AND CAT

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vein lie ventral to the bulla and must be protected when enlarging the osseous external acoustic meatus. A curette can first be used to remove the epithelium lining the meatus; then, a periosteal elevator can be used to remove soft tissue on the portion of the bulla that is to be removed. The elevator can then be used to gently retract the soft tissue and protect the artery and vein as the bone is removed with a rongeur or curette. In some cases, the bone can

be exceptionally sclerotic, and it may be necessary to use a high-speed burr to remove this bone. If a burr is used, extreme caution is necessary to prevent the burr from contacting the soft tissues. A bacterial culture sample of the bulla can be taken before curetting the cavity. This is likely to yield positive growth, possibly of more than one bacterium. Alternatively, the culture can be performed after

Management of Otitis Acute

Chronic

Management

Failed medical management

Canal open

Canal stenotic

Tumor

Malignant

Benign

LECR or TECA

TECA

Based on location of tumor

With otitis media

Without otitis media

TECA/LBO

TECA & LBO

FIGURE 1. Algorithm for management of otitis.

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the bulla has been curetted and flushed to detect any residual bacteria. Although a culture obtained this way is less likely to yield positive results, this approach may be more representative should complications arise after surgery. If the procedure is performed bilaterally, a culture sample should be taken from each bulla. If all necrotic debris present in the tympanic cavity is not removed, there is an increased risk for postoperative complications related to residual infection and possibly abscessation (Table 2). A soft rubber drain can be placed through a separate ventral incision into the bulla to allow for postoperative drainage. I find it useful to use magnification loops and a headlight to improve visualization of the cavity during this entire procedure.

Ventral Bulla Osteotomy VBO can be used in conjunction with TECA/ LECR or as a singular procedure to treat disease confined to the bulla. When VBO is used in conjunction with TECA or LECR, the patient must be repositioned. One study comparing VBO and TECA versus LBO and TECA found no difference in outcome or complication rate; thus, combining LBO with TECA is usually recommended.10 Because LBO cannot be combined with LECR, VBO is necessary upon discovery that the bulla should be drained. The most common reason to perform VBO alone is removal of inflammatory polyps in cats. Of note, the tympanic bulla in cats is divided by a thin septum of bone that separates the bulla into dorsal lateral and ventral medial compartments. A small opening in the septum allows for communication between the compartments.

SUMMARY Ear disease, whether acute or chronic, can be debilitating and painful, causing not only clinical signs related directly to the ears but often lethargy and anorexia. Treatment of diseases of the ear canal and middle ear can be complex and complicated because these diseases are often multifactorial. The anatomy of the ear can also make visualization difficult and an accurate diagnosis challenging. Because the ear canal and middle ear are more or less hidden from view, any disease process can often be advanced when first recognized. If an early accurate diagnosis is not made and appropriate medical treatment started, structural changes to the canal and/or bulla will occur, further complicating medical management. Lack of patient and owner compliance can also lead to failure of medical management. Surgery can play an important role in treating otitis externa and media and should be considered at each step of the way depending on the patientâ&#x20AC;&#x2122;s response to medical treatment. Tumors of the canal and bulla are almost always treated surgically. When there are anatomic changes to the canal and/or bulla, surgery can play an important role in treatment. As with any surgery, careful preoperative assessment of the patient is essential. Evaluating the extent of the disease, and potentially staging if malignancy is suspected, is central to a good outcome. A thorough understanding of the anatomy of the ear canal, bulla, and surrounding structures is

TABLE 2 Potential Complications Associated with Surgery of the Ear Canal and Tympanic Bulla COMPLICATION

LECR

Significant intraoperative hemorrhage Facial nerve paralysis (temporary or permanent)

LBO

VBO

Vestibular disease

Hypoglossal nerve paresis

Hornerâ&#x20AC;&#x2122;s syndrome

Incisional dehiscence/drainage Deafness

TECA

EAR DISEASE IN THE DOG AND CAT

++ ++

+ ++

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Glossary CT computed tomography LBO lateral bulla osteotomy LECR lateral ear canal resection MRI magnetic resonance imaging TECA total ear canal ablation VBO ventral bulla osteotomy

VET

imperative. Good surgical technique is important to diminish injury to vital blood vessels and nerves in the area; this will reduce the chance of both intraoperative and postoperative complications.

The FASTEST way to stop bleeding and keep it stopped.

REFERENCES

Recommended by veterinarians for use on biopsies, bleeding ulcers, dental procedures, and more.

1. Bruyette DS, Lorenz MD. Otitis externa and otitis media. Semin Vet Med Surg 1993; 8(1):3-9. 2. Rosser EJ. Causes of otitis externa. Vet Clin North Am Small Anim Pract 2004; 34(2):459-468. 3. Smeak DD, DeHoff WD. Total ear canal ablation clinical results in the dog and cat. Vet Surg 1986; 15(2):161-170. 4. Remedios AM, Fowler JD, Pharr JW. A comparison of radiographic versus surgical diagnosis of otitis media. JAAHA 1991; 27:183-188. 5. Love NE, Kramer RW, Spodnick GJ, Thrall DE. Radiographic and computed tomographic evaluation of otitis media in the dog. Vet Radiol Ultrasound 1995; 36(5):375-379. 6. Zepp CP. Surgical correction of diseases of the ear in the dog and cat. Vet Rec 1949; 61:643-647. 7. Mason LK, Harvey CE. Total ear canal ablation combined with lateral bulla osteotomy for end-stage otitis in dogs. Vet Surg 1988; 17(5):263-268. 8. McAnulty JF, Hattel A, Harvey CE. Wound healing and brain stem auditory evoked potentials after experimental total ear canal ablation with lateral tympanic bulla osteotomy in dogs. Vet Surg 1995; 24(1):1-8. 9. Devitt CM, Seim HB, Willer R, et al. Passive drainage versus primary closure after total ear canal ablation-lateral bulla osteotomy in dogs: 59 dogs (1985-1995). Vet Surg 1997; 26(3):210-216. 10. Sharp NJH. Chronic otitis externa and otitis media treated by total ear canal ablation and ventral bulla osteotomy in thirteen dogs. Vet Surg 1990; 19(2):162-166.

Mark Cofone

Mark Cofone, VMD, DACVS, is a staff surgeon and co-owner of the Veterinary Specialty Center of Delaware. He graduated with his VMD from the University of Pennsylvania, where he also completed his internship and surgical residency. He was a Senior Scientist at Ethicon, Inc., and for the past 20 years has been in private surgical practice.

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UNCOVERING THE CAUSE OF FEVER IN CATS

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FELINE-FRIENDLY ARTICLE

Uncovering the Cause of Fever in Cats Kenneth R. Harkin, DVM, DACVIM (Small Animal Internal Medicine) Kansas State University

The normal body temperature range in cats is 38.1°C to 39.2°C (100.5°F–102.5°F). Fever of unknown origin (FUO) in cats is classified as a temperature higher than 39.7°C (103.5°F) measured at least 4 times in a 2-week period without an identified cause.

TERMINOLOGY The term FUO is often overused in veterinary medicine, as the number of patients in which a true case of fever cannot be uncovered is relatively small. Veterinary patients are often described incorrectly as having FUO when routine diagnostic testing yields negative results. The term FUO should be reserved for patients in which no etiology is revealed after an extensive workup. FUO is also applied incorrectly when used to describe a fever that does not respond to empiric antibiotics. A response to antibiotics does not prove a bacterial cause for fever because a transient response may be associated with an anti-

shutterstock.com/Tom Wang

inflammatory effect of the antibiotic or the waxing/waning course of disease. It is important to remember that fever implies an internal resetting of the hypothalamic set point, whereas the elevated body temperature in hyperthermia results from outside causes.

Learn More Read Uncovering the Cause of Fever in Dogs in the July/August 2016 issue of Today’s Veterinary Practice, available at tvpjournal.com.

DIAGNOSTIC APPROACH In cats, the diagnostic approach to fever varies from that typically followed for dogs: In dogs, the approach tends to be orderly and algorithmic. In cats, diagnosis requires both categorical and algorithmic approaches. For many cats that present with fever, a thorough physical examination often

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Learn More Read the American Association of Feline Practitioners (AAFP) Feline Retrovirus Management Guidelines at www.catvets.com/ guidelines/practice-guidelines/retrovirusmanagement-guidelines.

reveals clues as to the etiology or, at least, to the organ system involved. For example:

• Purulent discharge or evidence of pain and bite marks can suggest a cat bite abscess. • Lymphadenomegaly is not pathognomonic for any one disease, but it points to a specific diagnostic test (lymph node aspiration) that may provide the diagnosis. • Icterus in a febrile cat should prompt a complete blood count (CBC) and blood smear evaluation (which may reveal the etiology, such as hemotropic mycoplasmosis or cytauxzoonosis) or serum biochemistry profile (which may help support a diagnosis of acute cholangiohepatitis).

In their retrospective study of severe neutrophilia (40 × 109/L–76 × 109/L), Langenstein and colleagues2 found that only 2 of 24 cats had a fever (>39.3°C [102.7°F]), despite 21 of 28 cats having an inflammatory disease. In most of the cats in these studies, diagnosis of the cause of fever would likely have been straightforward, with physical examination findings and/or results of routine testing (CBC, serum biochemistry profile, urinalysis, feline leukemia virus [FeLV] and FIV testing) guiding the diagnosis.

BOX 1 Causes of Persistent Fever in Cats

• Dyspnea or dull or absent lung sounds on thoracic auscultation should lead to a consideration of pyothorax, which warrants further evaluation with thoracic radiography and thoracentesis.

Infectious disease • P yelonephritis

• Renomegaly, hepatomegaly, or mesenteric lymphadenomegaly may prompt the need for abdominal imaging (radiographs or ultrasound) or fine-needle aspiration for cytologic evaluation.

• Feline infectious peritonitis

In some cats, however, the cause cannot be identified even after an extensive medical investigation that includes a thorough history and physical examination, imaging, and culture of various body fluids when indicated.

LITERATURE REVIEW Despite the notion that fever is a common clinical sign in cats, retrospective studies detailing the diagnostic workup in cats with FUO are lacking.

Identifying Cause In their study of factors associated with toxic neutrophils in cats, Segev and colleagues found fever

in 14% of patients (21/150).1 The authors named several diseases that would be expected to cause fever (but were not named specifically as the causes of fever in these patients), including pneumonia, feline immunodeficiency virus (FIV) infection, upper respiratory tract infection, bite wounds, peritonitis, pleural effusion, panleukopenia, and sepsis.

UNCOVERING THE CAUSE OF FEVER IN CATS

• Feline leukemia virus • Feline immunodeficiency virus • Panleukopenia virus • Parasitic infection • Upper respiratory tract infection • Herpesvirus • Infection secondary to bite/scratch wounds •S ystemic mycotic disease (eg, histoplasmosis, blastomycosis) Neoplastic disease • Lymphoma • Myeloproliferative disease Immune-mediated disease • Immune-mediated hemolytic anemia • Immune-mediated neutropenia • Pemphigus foliaceus Miscellaneous • Drugs (eg, penicillin, tetracycline)

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In a case series of 6 cats with renal abscess, only 3 cats were febrile, but renomegaly was a consistent finding, as was active sediment on urinalysis, further emphasizing the ability to localize findings based on physical examination and routine testing.3

Infectious Disease Based on review of published case studies, retrospectives, case reports, and review articles (cited throughout this text) in which fever is listed as a finding on physical examination, infectious disease appears to be the most common cause of fever in cats (Box 1). Bacterial Disease

Some of the published reports on bacterial infections describe a clinical presentation that does not follow what is generally expected for the organism.

• Dow and colleagues reported on 6 cats with salmonellosis. Four of the 6 cats were febrile, yet 2 had no signs referable to the gastrointestinal tract and a third had findings more consistent with acute kidney injury.4 • Giovannini and colleagues5 also reported on an outbreak of salmonellosis characterized by fever and anorexia without diarrhea in cats suspected of eating passerine birds (songbirds). In some instances, the clinical signs of a generalized bacterial infection are caused by an unexpected organism.

• In a retrospective case study, persistent fever was a prominent feature in 2 Siamese cats ultimately diagnosed with disseminated Mycobacterium avium complex infection. Diagnosis was straightforward, with identification of the organisms in aspirates of the spleen and/ or lymph nodes.6 Lymphadenomegaly was not pathognomonic for this infection, but provided the target for making the diagnosis. • Fever can be seen with tuberculous or non-tuberculous mycobacterial infections in cats, and although organisms are commonly seen in aspirate or biopsy samples of affected organs or subcutaneous nodules (Figure 1), it is possible for the organisms to be lost during processing of histology samples.7 Fungal Disease

Histoplasmosis can present with relatively vague clinical signs. In one study, 34% of cats with histoplasmosis were reported to be febrile.8 Only half of the cats had recognized pulmonary involvement, and only 25% had peripheral lymphadenomegaly. When pulmonary involvement and lymphadenomegaly are not present in a cat with histoplasmosis, the clinician may be faced with a febrile cat and no apparent diagnostic direction. In these patients, a liver, bone marrow, or splenic aspirate may be necessary to establish a diagnosis (Figures 2 and 3).

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FIGURE 1. Cytology of a lymph node aspirate demonstrating long, negative-staining bacilli within macrophages (arrows) from a cat with Mycobacterium species infection.

FIGURE 4. Cytology of a lymph node aspirate from a cat with Cytauxzoon felis infection. The macrophages are laden with schizonts (short arrow) and the macrophage on the left is rupturing to release merozoites, which will infect more macrophages (long arrow).

FIGURE 2. Cytology of a bone marrow aspirate from a cat with pancytopenia demonstrating multiple Histoplasma capsulatum organisms (arrows).

FIGURE 5. C. felis piroplasms are seen on this blood smear from a cat (arrows).

FIGURE 3. Cytology of a lymph node aspirate from a cat with histoplasmosis demonstrating large numbers of H. capsulatum organisms within macrophages (arrows).

FIGURE 6. Histology of a liver biopsy sample from a cat with toxoplasmosis demonstrating a hepatocyte containing numerous tachyzoites (arrow).

UNCOVERING THE CAUSE OF FEVER IN CATS

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Protozoal & Parasitic Disease

Cytauxzoonosis most commonly presents as a rapidly fatal febrile illness characterized by hemolytic anemia, lethargy, and icterus. In these patients, organisms are often found in red blood cells or tissue macrophages (Figure 4), but the organism is not always identified on a blood smear (Figure 5), resulting in lack of, or delayed, diagnosis.9 Toxoplasmosis (Figure 6), although typically an asymptomatic infection, can result in acute or chronic disease. Fever is common in both presentations, but with such an array of nonspecific clinical signs that diagnosis is often delayed.10 In a retrospective study of 100 cases of toxoplasmosis in cats in which the diagnosis was confirmed histologically over a 39-year period, fever was identified in 49 of 67 cats (73%) for which a rectal temperature was recorded.11 Viral Disease

Various viral diseases of cats can cause transient or persistent fever. Feline infectious peritonitis (FIP) was reported to result in fever in 120 of 215 cats (55.8%) in a recent retrospective study, with 43 of the cats presenting with a fever in excess of 40°C (104°F).12 In that study, 89% of cats with FIP had elevated globulins, although the degree of hyperglobulinemia may have been relatively subtle in some (median, 51.78 g/L; upper reference interval, 50 g/L). FIP was significantly more common in cats younger than 2 years.12 In the initial stage of infection, FIV may present with fever that persists for a few weeks before resolving, regardless of therapy.13 FeLV infections are associated with fever when the cat acquires a secondary infection or as a component of a paraneoplastic syndrome; however, fever is not typically caused by the primary viral infection itself.13 Although fever is a common component of the respiratory syndrome caused by herpesvirus and calicivirus infections, chronic persistent fever does not occur in the absence of upper respiratory disease and diagnosis is typically obtained with minimal testing.14,15 Borna disease virus, although rare, is reported to be present with fever in some cats, in addition to gait disturbances and behavioral changes.16 Avian influenza virus (H5N1) infection in cats reportedly produces fever, severe respiratory signs, and neurologic signs (convulsions and ataxia), but it is also rare.17

Zoonotic Disease Bartonellosis is recognized as a zoonotic disease in which the cat plays an important role. Experimental inoculation in cats, whether by blood transfusion or flea inoculation, has been shown to result in transient febrile illness, but it remains unclear what role chronic infection with Bartonella henselae or other Bartonella species would play in recurrent or persistent fever in cats.18 MARCH/APRIL 2017

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Learn More For more information on hyperbilirubinemia, read The Yellow Cat: Diagnostic & Therapeutic Strategies (September/October 2016), available at tvpjournal.com.

DIFFERENTIAL DIAGNOSIS: CATEGORICAL APPROACH The categorical approach to fever in cats involves stratifying the risks for various diseases based on a number of parameters. The emphasis is on differentials for fever when the diagnosis is not immediately obvious (eg, the kitten with a severe upper respiratory tract infection caused by herpesvirus or calicivirus). Important factors used to determine the relative risk for various diseases include (Box 2):

• Age, environment, travel history, and retrovirus status • Whether cat lives exclusively indoors or is allowed outside • If the cat goes outdoors, the extent of its roaming behavior (because the risk for certain infectious diseases increases dramatically in the roaming, active hunter) • Number of cats in the household

• In multicat households, status of the colony (eg, number of cats, hierarchy of the colony, retroviral status, recent additions); for example, FIP would be high on the differential list for a 9-month-old kitten with persistent fever (>2 weeks) that lives in a multicat household, but would be considered unlikely in a 12-year-old cat that has been living with 4 other cats of roughly the same age for its entire life. While this approach can include many different categories of cats, the following discussion focuses on the most common: young and older indoor cats in single-cat and multicat households and outdoor cats of all ages. Category 1: Young Cat, Lives Indoors, No Other Pets Given that infection is the most common cause of fever in cats, cats in this category are infrequently evaluated for disease that results in fever. Foreign body ingestion is more common in young, curious cats. Foreign bodies (eg, needles) that penetrate the oral cavity can result in secondary abscessation or cellulitis with resultant fever. While vomiting and inappetance—rather than fever—are the most common signs seen with a gastrointestinal foreign body, peritonitis can develop subsequent to perforation. The clinician should perform a careful inspection of the oral cavity, especially if the client reports that the cat is pawing at the mouth, drooling, or showing other signs of oral discomfort, and palpate the abdomen and intestinal tract if vomiting is present. FeLV and FIV testing should be performed if the status of the cat is unknown.

BOX 2 Fever in Cats: Questions Used to Determine Relative Risk For Disease • What is the cat’s age, environment, travel history, and retrovirus status? • Does the cat live exclusively indoors or is it allowed outside? • If the cat goes outside, how far does it roam? • H ow many cats are in the household? • In multicat households, what is the colony status: number of cats, hierarchy of colony, retroviral status, and recent additions?

UNCOVERING THE CAUSE OF FEVER IN CATS

FIP must be considered high on the list of differentials as a cause of persistent fever in cats younger than 1 year of age. Index of suspicion for FIP is even greater if hyperbilirubinemia and/or hyperglobulinemia is noted on a serum biochemistry profile. In cats that do not have an effusion, the diagnosis can be impossible to confirm except through biopsy (eg, liver).

Although it is beyond the scope of this article to discuss pros and cons of serologic testing for FIP, I prefer confirmation using polymerase chain reaction (PCR) assay for coronavirus

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on an effusion or histologic confirmation. Still, in most cases of FIP, the clinician should be able to collect enough supporting evidence for a presumptive diagnosis of FIP with a high level of confidence.

Whatever your dog brings home, it shouldn’t be fleas & ticks.

Histoplasmosis has been documented in cats housed exclusively indoors and should also be a consideration, but this diagnosis does not typically come to mind in the absence of respiratory signs with associated radiographic changes, ocular abnormalities, or lymphadenomegaly.

In some cats, the disease may be localized primarily to the bone marrow with some degree of bicytopenia or pancytopenia evident on CBC; in others, the organism may be found in aspirates of the spleen or liver, even in the absence of elevated liver enzymes. The clinician should consider including a urine antigen test (or urine and blood) for the detection of histoplasmosis in cats with vague clinical signs and persistent fever. Surgical site infection should be investigated as a possible cause of fever if the cat has had prior surgery (eg, ovariohysterectomy), especially recently.

Other infectious causes are rare in this category, and immunemediated disease is an uncommon cause of fever in cats. Category 2: Young Cat, Lives Indoors, Multicat Household All of the diseases listed in the previous category should also be considered in young, indoor cats living in multicat households (Table 1). FeLV and FIV testing is one of the first steps in the diagnostic workup. FIP should receive more consideration in this category, given the ubiquitous nature of feline enteric coronavirus. Even something as simple as evaluating packed cell volume (PCV) and total solids (TS) using a microhematocrit tube and refractometer may provide a rapid screen to include FIP on the differential list, if the TS count is elevated.

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In a multicat household where flea infestation is problematic, rapid screening of PCV and TS also provides information as to the possibility of infection by hemotropic mycoplasmal organisms (anemia and icteric serum). Of course, in both scenarios, additional testing is necessary to confirm the diagnosis or arrive at an alternate diagnosis. Bartonellosis is more likely in cats with flea infestation. Although serologic testing is of questionable value in understanding the relative risk of clinical bartonellosis, the clinician should consider some level of testing (PCR on blood, fluids, or tissue, with or without serologic testing) if:

• A diagnosis is elusive • Multiple cats have a febrile illness

Also available for cats.

• Pyogranulomatous disease is found on histology

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Cat bite abscesses or cellulitis may result from intercat aggression, which depends on the stability of the relationships among the cats in the household (or in spite of it), and the clinician should evaluate the cat for evidence of these causes of fever. Pyothorax may also result from intercat aggression. In one study, pyothorax was reportedly more common in cats from multicat households, with an almost fourfold increased risk compared with cats in singlecat households.19 The mean age of cats diagnosed with pyothorax was 3.8 years, and there was no difference in prevalence between indoor and outdoor cats.19

TABLE 1 Categorical Approach to FUO in Cats PRESENTATION

Young cat, lives indoors, no other pets

DIFFERENTIAL DIAGNOSIS

eline leukemia virus F Feline immunodeficiency virus Feline infectious peritonitis Oral, pharyngeal, or gastrointestinal foreign body (with secondary abscessation, cellulitis, or peritonitis) • Histoplasmosis • Surgical site infection • • • •

•B artonellosis (secondary to flea infestation) • C at bite wounds/abscess, cellulitis, Young cat, lives indoors, multicat household

or pyothorax (secondary to intercat aggression) • Feline leukemia virus • Feline immunodeficiency virus • Feline infectious peritonitis • Histoplasmosis • Surgical site infection •A cute cholangiohepatitis • Cancer unassociated with retroviral infection • Cat bite wounds/abscess, cellulitis, or

Older cat, lives indoors, multicat or single-cat household

pyothorax (secondary to intercat aggression) • Feline leukemia virus • Feline immunodeficiency virus • Feline infectious peritonitis • Histoplasmosis • Immune-mediated disease • Pancreatitis (acute, acute on chronic, chronic smoldering) • P yelonephritis • Cat bite wounds/abscess, cellulitis, or

Cat of any age, free to roam outdoors

• • • • • • •

pyothorax (secondary to intercat aggression) Cytauxzoonosis Feline immunodeficiency virus Feline leukemia virus Salmonellosis Toxoplasmosis Tularemia Yersinia pestis (plague)

UNCOVERING THE CAUSE OF FEVER IN CATS

Diagnosis of pyothorax may be elusive if the volume of effusion is insufficient to result in significant respiratory compromise or abnormalities on thoracic auscultation. Considering that both histoplasmosis and pyothorax may present with vague and subtle signs early in the course of disease and that contents of the thorax cannot be palpated (in contrast to the abdomen), thoracic radiographs should be considered in the workup of a cat with FUO even in the absence of obvious respiratory signs. Category 3: Older Cat, Lives Indoors, Multicat or Single-Cat Household Most older cats have been exposed to common viral pathogens, mounted a normal immune response to eliminate them, and have limited or no susceptibility. FeLV, FIV, and FIP are lesser considerations than in young cats, although testing for FeLV and FIV is always recommended in any sick cat if the retrovirus status is not known or in doubt. Cat bite wounds may be a problem in the multicat household. A thorough evaluation, including CBC, serum biochemistry profile, and urinalysis, is indicated in these cats when the diagnosis is not immediately evident. Pyelonephritis may be present in a cat with an obstructed ureter and a history of recurrent calcium oxalate urolithiasis, which is an example of how history may also help in the evaluation of potential differentials. Acute cholangiohepatitis, pancreatitis (acute, acute on chronic, chronic smoldering), histoplasmosis, cancer unassociated with retroviral infection and, to a much lesser degree, immune-mediated disease are additional differentials to consider in this category of cats.

Fever was identified in 4 of 33 cats with pancreatitis (mean age, 12.7 years) in a study by Stockhaus and colleagues.20 Given the often vague clinical signs associated with pancreatitis (hyporexia or anorexia is the most frequent complaint and, sometimes, the only historical clinical finding), the veterinarian may need to consider additional diagnostics, such as measurement of feline

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pancreatic lipase immunoreactivity or abdominal ultrasound, to confirm the diagnosis.20 Category 4: Cat of Any Age, Free to Roam Outdoors Cats that have free access to the outdoors are at highest risk for exposure to diseases associated with the predator–prey cycle, including vector-borne diseases. These cats may be more aggressively territorial and self-defensive and, thus, more prone to fighting with other cats. Cat bite abscess, tularemia, cytauxzoonosis, and salmonellosis (a distant fourth) are, in my experience, the most common conditions in cats with a fever in excess of 40°C (104°F) and usually over 40.5°C (105°F).

Careful physical examination to look for catbite abscess, wounds, or cellulitis is the first step when evaluating cats in this category. Although tularemia is most commonly reported in some midwestern states (ie, South Dakota, Kansas, Missouri, Oklahoma, Arkansas), the bacteria have been recognized throughout North America. Cats typically are infected through ingestion of infected rabbits, although tick-transmitted tularemia can occur.21 Tularemia is typically confirmed by serologic evidence of seroconversion, although the organism can be seen on cytology from aspiration of regional lymphadenomegaly in the case of tick transmission. Tularemia is a zoonotic disease, and precautions should be taken when handling a cat if infection with this organism is suspected. However, I am unaware of any reports of zoonotic transmission resulting from performing fine-needle aspiration. A blood smear is helpful to identify Cytauxzoon felis organisms in the red blood cells but is not always rewarding. If the cat is anemic, a blood smear can help identify hemotropic mycoplasma organisms, if present. A fecal and/or blood culture can be performed to confirm a diagnosis of salmonellosis if ingestion of passerine birds is suspected. Toxoplasmosis should also be considered as a differential for cats because of their predation.

Cats with multiorgan disease (any combination of pulmonary, hepatic, nervous system, and gastrointestinal signs), especially when combined with a persistent or relapsing fever, should be evaluated for toxoplasmosis. Serologic testing should document a high IgM (reciprocal titer >64) or a fourfold rise in IgG over 2 to 3 weeks.10

IN SUMMARY The diagnosis of fever in cats often involves investigation directed toward an infectious etiology. For cats housed indoors, the diagnostic differential list is fairly limited and, for many young cats, a diagnosis of FIP is often made. The veterinarian should consider all risk factors for individual cats (indoor, outdoor, multicat household, predator, time of year) when deciding which diagnostics to pursue. Categorizing cats based on these risk factors should help the veterinarian narrow the focus, optimize testing, and achieve a diagnosis. REFERENCES 1. Segev G, Klement E, Aroch I. Toxic neutrophils in cats: clinical and clinicopathologic features, and disease prevalence and outcome—a retrospective case control study. J Vet Intern Med 2006; 20:20-31. 2. Langenstein J, Bauer N, Moritz A. Extreme neutrophilia in cats— aetiology and prognosis. Tieraztl Prax Ausg K Klientiere Heimtiere 2015; 43(5):323-330. 3. Faucher MR, Theron ML, Reynolds BS. Renal abscesses in cats: six cases. J Feline Med Surg 2015. DOI: 10.1177/1098612X15613388. [Epub ahead of print] 4. Dow SW, Jones RL, Henik RA, Husted PW. Clinical features of salmonellosis in cats: six cases (1981-1986). JAVMA 1989; 194(10):14641466. 5. Giovannini S, Pewsner M, Hussy D, et al. Epidemic of salmonellosis in passerine birds in Switzerland with spillover to domestic cats. Vet Pathol 2012; 50(4):597-606.

Glossary CBC complete blood count FeLV feline leukemia virus FIP feline infectious peritonitis FIV feline immunodeficiency virus FUO fever of unknown origin PCR polymerase chain reaction PCV packed cell volume TS total solids

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Kenneth R. Harkin

PHOTO CREDIT: Rhea Anna

Kenneth R. Harkin, DVM, DACVIM (Small Animal Internal Medicine), is a professor and head of the Section of Medicine in the College of Veterinary Medicine at Kansas State University. His research interests include infectious diseases and immunology, with a special interest in leptospirosis. He currently lectures on gastroenterology, hematology, hepatology, and neurology.

6. Jordan HL, Cohn LA, Armstrong PJ. Disseminated Mycobacterium avium complex infection in three Siamese cats. JAVMA 1994; 204(1):90-93. 7. Gunn-Moore DA. Feline mycobacterial infections. Vet J 2014; 201:230-238. 8. Reinhart JM, KuKanich KS, Jackson T, Harkin KR. Feline histoplasmosis: fluconazole therapy and identification of potential sources of Histoplasma species exposure. J Feline Med Surg 2012; 14(12):841-848. 9. Birkenheuer AJ, Le JA, Valenzisi AM, et al. Cytauxzoon felis infection in cats in the mid-Atlantic states: 34 cases (19982004). JAVMA 2006; 228:568-571. 10. Lappin MR. Update on the diagnosis and management of Toxoplasma gondii infection in cats. Topics Comp Anim Med 2010; 25(3):136-141. 11. Dubey JP, Carpenter JL. Histologically confirmed clinical toxoplasmosis in cats: 100 cases (1952-1990). JAVMA 1993; 203(11):1556-1566. 12. Riemer F, Kuehner KA, Ritz S, et al. Clinical and laboratory features of cats with feline infectious peritonitis—a retrospective study of 231 confirmed cases (2000-2010). J Feline Med Surg 2016; 18(4):348-356.

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13. Hartmann K. Clinical aspects of feline retroviruses: a review. Viruses 2012; 4:2684-2710. 14. Thiry E, Addie D, Belak S, et al. Feline herpesvirus infection: ABCD guidelines on prevention and management. J Feline Med Surg 2009; 11:547-555. 15. Radford AD, Addie D, Belak S, et al. Feline calicivirus infection: ABCD guidelines on prevention and management. J Feline Med Surg 2009; 11:556-564. 16. Wensman JJ, Jaderlund KH, Holst BS, et al. Borna disease virus infection in cats. Vet J 2014; 201:142-149.

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17. Marschall J, Hartmann K. Avian influenza A H5N1 infections in cats. J Feline Med Surg 2008; 10:359-365.

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18. Breitschwerdt EB, Maggi RG, Chomel BB, et al. Bartonellosis: an emerging infectious disease of zoonotic importance to animals and human beings. J Vet Emerg Crit Care 2010; 20(1):8-30.

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19. Waddell LS, Brady CA, Drobatz KJ. Risk factors, prognostic indicators, and outcome of pyothorax in cats: 80 cases (1986-1999). JAVMA 2002; 221(6):819-824.

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Clifford “Kip” Berry, DVM, DACVR

20. Stockhaus C, Teske E, Schellenberger K, et al. Serial serum feline pancreatic lipase immunoreactivity concentrations and prognostic variables in 33 cats with pancreatitis. JAVMA 2013; 243:1713-1718.

*Limited Availability

21. World Health Organization. WHO guidelines on tularemia. Geneva, Switzerland: World Health Organization; 2007. http://apps.who.int/iris/bitstre am/10665/43793/1/9789241547376_eng.pdf.

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UNCOVERING THE CAUSE OF FEVER IN CATS

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VET REPORT VITALS

First Look: The Banfield VET Report shutterstock.com/Alexander Raths

Welcome to VET Report Vitals, a column focused on the results of the groundbreaking Banfield Veterinary Emerging Topics (VET) Report, “Are We Doing Our Part to Prevent Superbugs? Antimicrobial Usage Patterns Among Companion Animal Veterinarians.” This report, a collaboration between the NAVC and Banfield Pet Hospital, focuses on a critical topic: antimicrobial resistance. VET Report Vitals will present data from the report and put it in practical context.

The first annual Banfield Veterinary Emerging Topics (VET) Report was released earlier this year. Titled “Are We Doing Our Part to Prevent Superbugs? Antimicrobial Usage Patterns Among Companion Animal Veterinarians,” it emphasizes how antimicrobials can be critical for patient quality of life and survival. Its purpose, however, is to promote prudent antimicrobial use among companion animal practitioners by providing a baseline of antimicrobial usage data that may contribute to the discussion on how to achieve better concordance with published guidelines (Box 1).

VET REPORT VITALS

“Given the importance of antimicrobial drugs for combating infectious disease,” states the report, “the veterinary profession will undoubtedly continue to utilize antimicrobials to promote animal health. However, as understanding of AMR [antimicrobial resistance] and infectious disease treatment grows, antimicrobial usage will ideally become more judicious and specific to minimize AMR.” The report includes Banfield Pet Hospital data from 926 general practice hospitals in 43 states, with approximately 135,000 dog visits each week and a provider base of 3,850 veterinarians. Urinary tract infection (UTI) and respiratory tract infection (RTI) data from canine patients were extracted and evaluated. Highlights of the report’s findings include: Low awareness of and adherence to guidelines. Although guidelines have been developed to direct treatment of common companion animal infections, low awareness of these guidelines among veterinarians suggests poor concordance of usage patterns with guideline recommendations.

VET REPORT VITALS

The data show that 67.1% of nonrecurrent urinary infections and 44.2% of recurrent urinary infections received a guideline-concordant antimicrobial. The data also show that 79.6% of canine infectious respiratory disease episodes and 21.7% of bronchitis episodes were treated with a guideline-concordant antimicrobial. Antimicrobial use in UTIs. The VET Report shows that in 2015, 32,226 episodes of canine UTI were diagnosed, of which 95.2% were determined to be nonrecurrent in nature. The remainder of these episodes (4.8%) were preceded by 2 or more UTIs in the previous year. A urine culture and susceptibility (C&S) test was ordered for 6.2% of nonrecurrent and 24.6% of recurrent episodes.

The report continues with a breakdown of data showing the frequency of in-hospital antimicrobial use for canine UTIs, in which a single antimicrobial was dispensed, by infection recurrence and C&S order status. It also shares the first-line antimicrobial options recommended by the International Society for Companion Animal Infectious Diseases (ISCAID) for canine UTIs. Antimicrobial use in RTIs. In 2015, of 27,046 episodes of canine bacterial RTI in which antimicrobials were dispensed, 95.1% were classified as canine infectious respiratory disease complex (CIRD) and 4.9% as canine bacterial bronchitis.

Banfield has always been dedicated to using its extensive data to provide insights to the profession on topics that can improve veterinary care for pets. The first annual Banfield Veterinary Emerging Topics (VET) Report, supported by the collaborative educational efforts of the NAVC, focuses on a critical topic: antimicrobial resistance. It is titled “Are We Doing Our Part to Prevent Superbugs? Antimicrobial Usage Patterns Among Companion Animal Veterinarians.” “We are proud to team up with the NAVC on the 2017 VET Report to raise awareness about the critical topic of antimicrobial resistance in companion animal practice and how veterinarians can address it in their own practices,” said Dr. Karen Faunt, Vice President of Medical Quality Advancement at Banfield Pet Hospital. The full report is available at Banfield.com/VETReport or VetFolio.com/VETReport.

VET REPORT VITALS

The report continues with a breakdown of the data showing the frequency of in-hospital antimicrobial use for canine bacterial RTIs, in which a single antimicrobial was dispensed, by diagnosis. It also shares the ISCAID-recommended first-line antimicrobial options for canine bacterial RTIs. The report includes detailed data on usage patterns, as well as a discussion of guideline concordance opportunities. Ending with a solutions-based approach, it guides readers through the science of quality improvement and a model that any veterinary professional can use to create behavior change in their own practice to improve medical quality. A visual summary of the report’s highlights can be found on page 90.

BOX 1. What Are the Guidelines? Published guidelines on the judicious use of antimicrobials in veterinary medicine include: •A merican Association of Feline Practitioners/ American Animal Hospital Association. Basic guidelines of judicious therapeutic use of antimicrobials. Available at: avma.org/KB/Policies/Pages/AAFPAAHA-Basic-Guidelines-of-JudiciousTherapeutic-Use-of-Antimicrobials.aspx. •A merican Veterinary Medical Association. Do’s and don’ts: antimicrobial therapy. Available at: avma.org/KB/Resources/ Documents/AntibioticDoDonts_DOGpdf.pdf. •A merican Veterinary Medical Association. Judicious therapeutic use of antimicrobials. Available at: avma. org/KB/Policies/Pages/JudiciousTherapeutic-Use-of-Antimicrobials.aspx. •H illier A, Lloyd DH, Weese JS, et al. Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases). Vet Dermatol 2014;25:163-175, e142-e163. •W eese JS, Giguère S, Guardabassi L, et al. ACVIM consensus statement on therapeutic antimicrobial use in animals and antimicrobial resistance. J Vet Intern Med 2015;29:487-498.

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Veterinary Emerging Topics (VET) Report:

The Issue

Are We Doing Our Part to Prevent Superbugs? Antimicrobial Usage Patterns among Companion Animal Veterinarians

Key taKeaway Antimicrobial resistance (AMR) among bacteria is a growing threat to public health. Our profession should strive for responsible antimicrobial use, including improved adherence to established guidelines. By better aligning prescribing practices with existing guidelines, we can promote the health of pets and people who care for them by mitigating our contribution of AMR.

The Data

awareness among veterinarians can be increased

45%

62%

88%

are concerned about antimicrobial-resistant infections1

feel that antimicrobials in small animal practice impact AMR1

are unaware of the 3 existing sets of antimicrobial use guidelines; urinary infections,2 superficial bacterial folliculitis3 and respiratory infections4

prescription patterns can be improved

The Implications

In 2015, guideline-recommended first-line antimicrobials were not prescribed for5:

32.9%

55.8%

20.4%

78.3%

of canine non-recurrent urinary infections

of canine recurrent urinary infections

of canine infectious respiratory disease episodes

of canine bronchitis episodes

what does a rise in amr mean? Clients

Veterinarians

Less effective treatments for sick pets

Decreasing efficacy of available drugs

Increased veterinary bills

Threatens freedom to practice as we choose

Risk of AMR transmission from their pets

Zoonotic spread of AMR

The Approach

we need to maKe the invisible visible… Visible

Invisible

: Immediate patient needs : Client expectations

: Public health impacts : Antimicrobial resistance and long-term efficacy : Cumulative patient outcomes

…and balance priorities

quality improvement cycle PLAN – What you aim to achieve and what you will need to do and measure DO – Implement the plan STUDY – Try to

understand all outcomes

ACT – Make adjustments as needed

Download the full report at Banfield.com/VETreport or vetfolio.com/vetreport 1. AVMA Task Force for Antimicrobial Stewardship in Companion Animal Practice. Understanding companion animal practitioners’ attitudes toward antimicrobial stewardship. J Am Vet Med Assoc 2015;247:883-884. 2. Weese JS, Blondeau JM, Boothe D, et al. Antimicrobial use guidelines for treatment of urinary tract disease in dogs and cats: antimicrobial guidelines working group of the international society for companion animal infectious diseases. Vet Med Int 2011;2011. 3. Hillier A, Lloyd DH, Weese JS, et al. Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases Vet Dermatol 2014;25:163-175, e142-163. 4. Lappin MR. Antimicrobial Use Guidelines for Treatment of Respiratory Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases. Proceedings of the ACVIM Forum, Denver, CO 2016. 5. Banfield Pet Hospital/North American Veterinary Community. Veterinary Emerging Topics Report: Are We Doing Our Part to Prevent Superbugs? Antimicrobial Usage Patterns among Companion Animal Veterinarians. Portland, OR: Banfield Pet Hospital, 2016.

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IMAGING ESSENTIALS

Small Animal Abdominal Ultrasonography: The Spleen Elizabeth Huynh, DVM, and Clifford R. Berry, DVM, DACVR University of Florida

Welcome to our series of articles on small animal abdominal ultrasonography. The initial articles provided an overview of basic ultrasonography principles and a discussion about how to perform a sonographic tour of the abdomen. The rest of the series discusses ultrasound evaluation of specific abdominal organs/systems. Read the other small animal abdominal ultrasonography articles published in Today’s Veterinary Practice at tvpjournal.com.

Anatomically, the spleen is divided into 3 parts (Figure 1):

• Dorsal extremity (left craniodorsal) • Body (mid-abdominal) • Ventral extremity (right mid-abdomen and slightly caudoventral) In cats, however, these 3 parts are not commonly specified because the spleen is smaller, superficial, and located in the left cranial abdomen. Along the visceral surface border of the spleen, the hilum is surrounded by fat, where splenic

vessels can be found. The splenic portal veins can be seen originating from the splenic hilum and can be traced between the stomach and colon to a common confluence that then enters into the portal vein. The splenic arteries are not distinguishable without color Doppler. Landmarks that help identify the location of the spleen include the stomach, descending colon, and left kidney:

• The stomach is located cranial and medial to the spleen. • The left colic flexure and transverse colon are located dorsal (far field), medial and caudal to the body of the spleen (Figure 1). • The left kidney is located dorsal, medial (far field) and caudal to the spleen.

NORMAL ULTRASONOGRAPHIC FEATURES The spleen is an elongated, solid organ. Its size is highly variable in dogs but more fixed and much smaller in cats. German shepherds and greyhounds have a larger spleen than other canine breeds.1 MARCH/APRIL 2017

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FIGURE 1. Long-axis sagittal images of a normal spleen. The dorsal extremity can be seen in the far field (between arrows in A). The body can be seen along the left lateral side adjacent to the stomach (B). The ventral extremity can be seen in the far field (arrow in C).

In cats, the spleen is neither thick nor long, measuring less than 1 cm in thickness and 4 to 6 cm in length (Figure 2).1 The feline spleen is located in the near field. When the transducer is positioned in long axis relative to the cat (craniocaudal), the spleen will be a short-axis triangular shape similar to that seen on ventrodorsal abdominal radiographs.

In dogs, the splenic parenchyma is slightly hyperechoic relative to the adjacent liver and mesenteric fat; in cats, it is isoechoic to hypoechoic to the surrounding fat. The spleen has an outer hyperechoic capsule. It is normally homogeneous in echotexture, but when using a high-frequency linear array transducer, the

The canine spleen is found along the left cranial and ventral abdominal wall that parallels the greater curvature of the stomach within the greater omentum. Because the spleen is only attached by the gastrosplenic ligament of the greater omentum, its position in dogs can be variable. The feline spleen is located in the left cranial and lateral abdomen, caudal and lateral to the stomach. The left lobe of the pancreas in cats is deep and medial to the spleen; it is larger than the canine left pancreatic lobe. The left lobe of the pancreas in cats is more readily seen on both ultrasonography and abdominal radiography when compared with dogs (Figure 3).

FIGURE 2. Long-axis (relative to the patient) sagittal image of a normal spleen in a cat.

IMAGING ESSENTIALS

FIGURE 3. Ventrodorsal radiograph of a normal abdomen in a cat. Note the clear demarcation between the spleen (white arrowheads) and the left lobe of the pancreas (black arrowheads).

IMAGING ESSENTIALS

spleen can have a coarser architecture and more heterogeneous appearance (Figure 4).

Transducer Motions

Changes in the size, shape, echogenicity, and echotexture of the spleen may be a normal response and may be sonographically indistinguishable from a significant pathologic process. A normal scan does not equate with the absence of disease.

Wielding the transducer is an integral part of any ultrasound examination. When performing an abdominal ultrasound exam, there are 3 primary types of transducer movements: • Distance motion: The transducer is slid along the abdomen in a cranial-caudal, lateral, or dorsal-ventral direction. •N ondistance, angular motion: The transducer is held in place while the angle is changed.

PREPARATION AND SCANNING TECHNIQUE Examination of the spleen is part of a comprehensive routine ultrasound examination of the entire abdomen. Before beginning the examination, clip the patient’s hair and apply ultrasonic gel to the skin. Starting at the craniodorsal extremity of the spleen along the cranial border, use a distance motion to slide the transducer along the abdominal wall from the left cranial abdomen to the left caudal abdomen until the entire cranial border of the spleen has been evaluated (see Transducer Motions). In deep-chested animals, an intercostal leftsided approach through the 11th and 12th intercostal spaces may be needed to image the dorsal extremity of the spleen. In dogs without hepatomegaly or gastric distension, the dorsal extremity of the spleen is usually located deep to the 11th to 13th ribs, cranial to the left kidney, and often folds medially onto itself. For cats, sweep the left cranial abdomen in a right to left distance motion, just caudal to the stomach.

• Nondistance, rotational motion: The transducer is held in place but is rotated very slightly (usually millimeters).

1. Evaluate the cranial border of the spleen (transducer in sagittal plane and spleen is in transverse plane) by moving in a left to right direction along the cranial border of the spleen. Once on the right side of the abdomen, move the transducer caudal and then in a distance motion back across the abdomen (right to left) in the middle of the spleen, ensuring some overlap between the cranial pass and the current middle pass. 2. Once back to the dorsal extremity of the spleen, move the transducer caudally along the caudal border. 3. Move the transducer in a distance motion from left to right all the way through the caudoventral extremity. 4. From there the continuation can be variable, and the tip of the ventral extremity may be

FIGURE 4. Long-axis sagittal images of the spleen in a cat with an enlarged splenic lymph node. Note the coarse echotexture when a linear array transducer is used (A) compared with a microconvex transducer (B).

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found anywhere from alongside the left wall of the urinary bladder to curving ventrally toward the right ventral mid-abdominal wall. In cats, the entire spleen is usually visible just deep to the left cranial abdominal wall. Evaluate any abnormalities in both long- and short-axis views.

DIFFERENTIAL DIAGNOSIS OF SPLENIC DISEASES Diseases of the spleen fall into 1 of 4 categories (see Differential Diagnosis of Splenic Conditions):

• Focal or multifocal disease • Increased spleen size with no parenchymal alterations

Differential Diagnosis of Splenic Conditions • Focal or multifocal disease (nodules and/or masses) — H ematoma: from trauma, lymphoid hyperplasia, vascular tumor2,3 — N odular (lymphoid) hyperplasia4 — E xtramedullary hematopoiesis — P rimary neoplasia: Lymphoma, histiocytic sarcoma, hemangiosarcoma, hemangioma, fibroma, fibrosarcoma, extraskeletal osteosarcoma, myxosarcoma, myelolipoma, lipoma, liposarcoma, leiomyoma, leiomyosarcoma 5-8 — M etastatic tumor 9 — G ranuloma — Abscess10,11 • Increase in size without parenchymal alterations — Anesthetic agents (tranquilizers)12 — N odular (lymphoid) hyperplasia4 — E xtramedullary hematopoiesis — Autoimmune hemolytic anemias — Chronic anemias — H ematopoietic neoplasia: Mast cell tumor, lymphoma, histiocytic sarcoma 6-8

• Normal splenic ultrasound without parenchymal alterations

Focal or Multifocal Splenic Diseases Nodular (Lymphoid) Hyperplasia and Extramedullary Hematopoiesis

The ultrasound appearance of nodular hyperplasia varies from hypoechoic to isoechoic nodules (Figure 5) that are usually sharply marginated and typically have no other parenchymal abnormalities. In addition, areas of hyperplasia can appear as an isoechoic mass because of changes in splenic echotexture or shape or increased echogenicity.4 Extramedullary hematopoiesis can look similar to nodular hyperplasia, so cytology is required to differentiate between the two. Typically these lesions do not break the normal margins or extend beyond the normal splenic capsule; however, they can create a large mass effect as previously reported.4

• Diffuse nodular disease or inhomogeneous alterations in parenchyma

Myelolipoma

— H emangioma, hemangiosarcoma

Myelolipomas are benign, irregularly shaped or rounded, hyperechoic foci of varying sizes. They can be found at the splenic hilum along the visceral border at the exit of the splenic portal vessels or, less commonly, within the splenic parenchyma (Figure 6).13 Myelolipomas cannot be distinguished from other poorly shadowing hyperechoic foci in the spleen. These lesions are more common in geriatric dogs but are occasionally seen in geriatric cats.14

— R ound cell neoplasia: Mast cell tumor, lymphoma, histiocytic sarcoma 6-8 — G ranulomatous disease — H istoplasmosis — N odular (lymphoid) hyperplasia4 — Amyloidosis • N ormal splenic ultrasound without parenchymal alterations — Round cell neoplasia

Dystrophic Mineralization

— Lymphoid hyperplasia — S plenitis — E xtramedullary hematopoiesis

• Diffuse nodular disease or inhomogeneous parenchymal changes

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Focal areas of dystrophic mineralization can be identified as hyperechoic speckles and thin lines throughout the splenic parenchyma. The lesions

IMAGING ESSENTIALS

FIGURE 5. Long-axis sagittal images showing the varied appearance of nodular (lymphoid) hyperplasia in a mixedbreed dog (A) and an American pit bull terrier (B). Note the small, ill-defined, hyperechoic foci throughout the splenic parenchyma (arrows) in A and the large, well-defined, hypoechoic mass in B.

are consistent with vascular arterial changes and dystrophic mineralization secondary to chronic endocrinopathies such as hypothyroidism, diabetes mellitus, and hyperadrenocorticism.1 Focal Infarction

Splenic infarction occurs secondary to embolism or thrombosis within the splenic artery (Figure 7). In dogs, it has been described with bacterial endocarditis, hypercoagulable conditions secondary to liver disease, renal disease (amyloidosis in shar-peis), hyperadrenocorticism, neoplasia, and thrombosis associated with cardiovascular disease.15-17

color Doppler evaluation. Then, as the area undergoes revascularization and fibrosis, they ultimately shrink and the splenic shape becomes distorted. Infarctions can be poorly marginated, hypoechoic, or complex, acutely indistinguishable from other focal splenic lesions.15-18

Initially, splenic infarctions result in focal hypoechogenicity with lack of blood supply as seen on

FIGURE 6. Long-axis sagittal image of the spleen in an otterhound showing myelolipomas in the splenic hilum. There are two irregularly shaped, hyperechoic foci (black arrowheads) without distal acoustic shadowing. These structures are located at the splenic hilum, surrounding the splenic portal veins (white arrowheads) and along the visceral margin of the spleen.

FIGURE 7. Long-axis sagittal images of an enlarged infarcted spleen in a collie. The splenic artery is abnormally distended with echogenic material within its lumen (arrowhead in A). No splenic arterial blood flow is detected within the spleen using color Doppler (arrowheads in B).

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Circular, hypoechoic or anechoic, irregularly delineated masses have also been described in dogs and humans.15,18 After 4 to 7 days, blood clots can become hyperechoic with collateral vessels surrounding them. Diagnostic differentials for this lesion include nodular hyperplasia, abscess, hematoma undergoing clot organization or lysis, and neoplasia. Abscess

Splenic abscesses are uncommon. They can be focal or multifocal, and their appearance varies from poorly marginated, hypoechoic lesions to complex lesions with variable cystic components and echogenic debris.10,11,19 Distal acoustic enhancement is variable and depends on the viscosity of the fluid. If hyperechoic foci with or without comet-tail artifacts are present within the lesion, gas-forming microorganisms should be suspected (Figure 8). Hematoma

Hematomas can be caused by abdominal trauma, clotting disorders, or splenic neoplasia (hemangiosarcoma or lymphoma). They may happen within the parenchyma, subcapsular region, and/or adjacent to the spleen. Splenic margination may be altered if the lesion is large or close to the surface. These lesions are hyperechoic initially in intraparenchymal hemorrhage and anechoic to hypoechoic with larger collections of unclotted blood.20 Clotted blood within a hematoma

FIGURE 8. Long-axis sagittal image of the spleen in a mixed-breed dog. The parenchyma contains multiple, ill-defined hypoechoic foci throughout. There is a large abscess within the parenchyma, characterized by irregularly shaped, hyperechoic foci (arrows) with distal reverberation artifact consistent with gas.

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may appear isoechoic or hyperechoic, gradually becoming hypoechoic relative to the splenic parenchyma.21 Hematomas can also have internal septation and cavitations, and differentiation from tumors such as hemangiosarcoma is not possible. Primary Neoplasia

Hemangiosarcomas are the most commonly diagnosed neoplasia in the canine spleen. Other splenic neoplasias include histiocytic sarcoma, malignant histiocytosis, leiomyosarcoma, fibrosarcoma, undifferentiated sarcoma, extraskeletal osteosarcoma, chondrosarcoma, liposarcoma, myxosarcoma, rhabdomyosarcoma, and fibrous histiocytoma. In cats, splenic neoplasias include mast cell tumor, lymphoma, myeloproliferative disease and, less commonly, hemangiosarcoma. The ultrasonographic appearance of splenic neoplasia is variable and can include splenomegaly or focal mass lesions, which are commonly poorly defined, anechoic, hypoechoic, targetlike,22 or complex, similar to those of the liver. Following are the characteristic features of some splenic neoplasias:

â&#x20AC;˘ Hemangiosarcoma is the most common mass lesion of the spleen in dogs.23,24 Hemangiosarcomas have variable amounts of anechoic to hyperechoic areas throughout (Figure 9), occasionally with weak distal acoustic enhancement.5,25 Hemoperitoneum is a common sequela to splenic hemangiosarcoma, and this tumor is the most common cause of acute nontraumatic hemoperitoneum in

FIGURE 9. Long-axis sagittal image of the spleen in a golden retriever with hemangiosarcoma. There is a large, irregularly shaped, well-demarcated, heterogeneous mass causing distortion of the splenic capsule in the far field. Note the continuation of the more normal splenic parenchyma into this mass (arrowhead).

IMAGING ESSENTIALS

dogs.26 Hemangiosarcomas can be large and cavitated, with the cavitations typically central secondary to necrotic centers. Differentials include hematoma and nodular hyperplasia.

• Lymphoma typically is a diffuse disease of the spleen, but it can sometimes form focal masses that may distort the splenic contour or cavitate if the masses are large (Figure 10).7,25 Hemorrhagic abdominal effusion may also be present.7 In dogs, the abdominal lymph nodes (eg, medial iliac, hepatic, and mesenteric) are often markedly enlarged. • Malignant histiocytosis, malignant fibrous histiocytoma, and histiocytic sarcoma have multiple well-defined, hypoechoic nodules that may distort the splenic margin (Figure 11).27 Abdominal lymphadenopathy may be present. The spleen is the most common organ involved, followed by the

liver. The pancreas, kidneys, adrenal glands, ovaries, and gastrointestinal tract may also be affected.27

• Mast cell tumors infiltrating the spleen cause splenomegaly with diffuse hypoechogenicity or one or more hypoechoic nodules (Figure 12).28 Occasionally, the spleen may appear normal on ultrasound.29 In cats, there may be splenomegaly only, a diffusely hypoechoic spleen, a mottled and irregular spleen, or a spleen containing hypoechoic or hyperechoic nodules.25,28 • Metastatic carcinoma appears as solitary, welldefined, anechoic to hypoechoic nodules in cats25 and can appear as target lesions in dogs.22 • Multiple myeloma is a systemic disease in which multiple, small hyperechoic nodules can be seen in dogs, but the spleen may appear normal in cats.30

FIGURE 10. Long-axis sagittal images of the spleen in 3 dogs with lymphoma. “Leopard spots” in a German shepherd (A). Note the multiple to coalescing, oval-shaped, hypoechoic foci throughout the splenic parenchyma. Mottled parenchyma in a Pomeranian (B). Oval-shaped, well-defined, heterogeneously hypoechoic mass along the visceral border of the spleen in a shih tzu (arrowheads in C). Note the clear demarcation between the more normal splenic parenchyma and the mass (arrow). (D). Same dog as in C. The spleen is noted in the near field at the end of the splenic border (white arrow). There is a hypoechoic oval structure (+ signs denoting margins) consistent with a splenic lymph node. The lymph node is surrounded by hyperechoic mesentery (black arrowheads) consistent with regional inflammation or cellular infiltration.

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Generalized Splenic Diseases Splenic Torsion

Splenic torsions cause severe splenomegaly with a coarse, diffuse “lacy,” hypoechoic to anechoic parenchymal pattern with interspersed linear echoes.15,17,31 Torsion can also be seen as hypoechoic overall with small hyperechoic speckles (gas) throughout the parenchyma, giving it a “starry night” appearance. These appearances are caused by splenic congestion when the spleen rotates along its pedicle of the greater omentum, cutting off the venous outflow and ultimately leading to progressive active congestion and eventual infarction. As a result, the splenic veins near the hilum are also enlarged from venous outflow tract obstruction. The mesenteric fat around the hilus is often hyperechoic and hyperattenuating. Anechoic or slightly echogenic fluid may be seen adjacent to the spleen. In chronic splenic torsion, foci of hyperechogenicity with distal acoustic enhancement may be seen; this represents gas secondary to gas-producing bacteria causing an abscess.32 Splenic torsion is a disease of dogs (typically large breeds) and not cats. Acute Systemic Infectious Disease (Bacterial or Fungal)

Infectious splenitis may cause splenomegaly with normal to reduced echogenicity. Infectious or inflammatory splenitis is seen as hypoechogenicity

FIGURE 11. Short-axis transverse image of the spleen in a Jack Russell terrier with histiocytic sarcoma. Multifocal, round, well-defined, heterogeneously hypoechoic masses can be seen throughout the splenic parenchyma, mildly distorting the splenic capsule.

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and severe splenomegaly. In severe, acute inflammation, the spleen is diffusely hypoechoic and might have a mottled, heterogeneous appearance.14,16 Extramedullary Hematopoiesis and Lymphoid Hyperplasia

These diffuse non-neoplastic diseases can appear as normal to reduced echogenicity in dogs and can be normal in echogenicity in cats. Hypoechoic nodules may be present.25 Cats with extramedullary hematopoiesis, lymphoid hyperplasia, or both can have splenomegaly with normal echogenicity, hypoechoic nodules, or mottling.25

Diffuse Neoplastic Disease Common diffuse splenic neoplasias include lymphoma and mast cell tumor. These neoplasias, along with malignant histiocytic, myelomatous, and leukemic infiltrations, may reduce splenic echogenicity, or the parenchyma may appear normal.29,33 Following are the ultrasonographic characteristics of lymphoma and mast cell tumor.

• Lymphoma may produce a spectrum of abnormalities with diffuse lymphomatous infiltration ranging from no abnormalities to splenomegaly; multiple, variably sized hypoechoic nodules; diffuse increased or decreased echogenicity with coarse echotexture; or multiple hypoechoic nodules often referred to as a “honeycomb pattern,” “moth-eaten appearance,” “spotted spleen,” or “leopard spots” (Figure 10).

FIGURE 12. Long-axis sagittal image of the spleen in a mixed-breed dog with mast cell tumor. A large, heterogeneously hypoechoic, ill-defined mass can be seen in the splenic parenchyma (arrowheads). In addition, there is a round, heterogeneously hypoechoic mass within the mesentery, adjacent to the splenic parenchyma, that is presumed to be a metastatic splenic lymph node (arrow).

IMAGING ESSENTIALS

• Mast cell tumors may appear normal or may look similar to the patterns (multiple hypoechoic to anechoic areas) in cats with splenic lymphoma or myeloproliferative disease (Figure 12).33 These diseases cannot be distinguished from each other. However, mesenteric lymphadenopathy and abdominal effusion are more likely in cats with lymphoma. Splenic mast cell tumors in cats are more likely to have an irregular contour.

Elizabeth Huynh

Elizabeth Huynh, DVM, is a diagnostic imaging resident and graduate student at University of Florida College of Veterinary Medicine. Her interests include ultrasonography, cross-sectional imaging, and nuclear medicine. She received her DVM from Ross University, finished her clinical year at Ohio State University, and completed a diagnostic imaging internship at Animal Specialty and Emergency Center in Los Angeles, California.

References 1.

Mahoney P. Spleen. BSAVA Manual of Canine and Feline Ultrasonography. Quedgeley, UK: British Small Animal Veterinary Association; 2012.

2. Wrigley RH, Konde LJ, Park RD, et al. Clinical features and diagnosis of splenic hematomas in dogs: 10 cases (1980-1987). J Am Anim Hosp Assoc 1989; 25:371-375. 3. van Sonnenberg E, Simeone JF, Mueller PR, et al. Sonographic appearance of hematoma in liver, spleen, and kidney: a clinical, pathologic, and animal study. Radiology 1983; 147:507-510. 4. Stowater JL, Lamb CR, Schelling SH. Ultrasonographic features of canine hepatic nodular hyperplasia. Vet Radiol 1990; 31:268-272.

Clifford R. Berry

Clifford R. Berry, DVM, DACVR, is a professor of diagnostic imaging at University of Florida College of Veterinary Medicine. His research interests include cross-sectional imaging of the thorax, nuclear medicine, and biomedical applications of imaging. He received his DVM from University of Florida and completed a radiology residency at University of California–Davis.

5. Wrigley RH, Park RD, Konde LJ, et al. Ultrasonographic features of splenic hemangiosarcoma in dogs: 18 cases (1980-1986). JAVMA 1988; 192:1113-1117. 6. Wrigley RH, Konde LJ, Park RD, et al. Ultrasonographic features of splenic lymphosarcoma in dogs: 12 cases (1980-1986). JAVMA 1988; 193:1565-1568. 7. Lamb CR, Hartzband LE, Tidwell AS, et al. Ultrasonographic findings in hepatic and splenic lymphosarcoma in dogs and cats. Vet Radiol 1991;32:117-120. 8. Cruz-Arambulo R, Wrigley R, Powers B. Sonographic features of histiocytic neoplasms in the canine abdomen. Vet Radiol Ultrasound 2004;45:554-558. 9. Murphy JF, Bernardino ME. The sonographic findings of splenic metastases. J Clin Ultrasound 1979;7:195-197.

22. Cuccovillo A, Lamb CR. Cellular features of sonographic target lesions of the liver and spleen in 21 dogs and a cat. Vet Radiol Ultrasound 2002; 43:275-278. 23. Feeney DA, Johnston GR, Hardy RM. Two-dimensional, gray-scale ultrasonography for assessment of hepatic and splenic neoplasia in the dog and cat. JAVMA 1984; 184:68-81. 24. Nyland TG, Kantrowitz BM. Ultrasound in diagnosis and staging of abdominal neoplasia. Contemp Issues Small Anim Pract 1986; 6:1-24.

10. Dubbins PA. Ultrasound in the diagnosis of splenic abscess. Br J Radiol 1980;53:488-489.

25. Hanson JA, Papageorges M, Girard E, et al. Ultrasonographic appearance of splenic disease in 101 cats. Vet Radiol Ultrasound 2001; 42:441-445.

11. Konde LJ, Lebel JL, Park RD, et al. Sonographic application in the diagnosis of intraabdominal abscess in the dog. Vet Radiol 1986;27:151-154.

26. Aronsohn MG, Dubiel B, Roberts B, Powers BE. Prognosis for acute nontraumatic hemoperitoneum in the dog: a retrospective analysis of 60 cases (2003-2006). JAAHA 2009; 45:72-77.

12. O'Brien RT, Waller KR III, Osgood TL. Sonographic features of druginduced splenic congestion. Vet Radiol Ultrasound 2004;45:225-227.

27. Ramirez S, Douglass JP, Robertson ID. Ultrasonographic features of canine abdominal malignant histiocystosis. Vet Radiol Ultrasound 2002; 43:167-170.

13. Schwarz LA, Penninck DG, Gliatto J. Canine splenic myelolipomas. Vet Radiol Ultrasound 2001;42:347-348. 14. Sandler CH, Langham RF. Myelolipomas of the spleen in a cat. JAVMA 1972;160:1101-1103. 15. Schelling CG, Wortman JA, Saunders HM. Ultrasonic detection of splenic necrosis in the dog: three case reports of splenic necrosis secondary to infarction. Vet Radiol 1988; 29:227-233. 16. Ellison GW, King RR, Calderwood-Mays M. Medical and surgical management of multiple organ infarctions secondary to bacterial endocarditis in a dog. JAVMA 1988; 193:1289-1291. 17. Hardie EM, Vaden SL, Spaulding K, et al. Splenic infarction in 16 dogs: a retrospective study. J Vet Intern Med 1995; 9:141-148. 18. Goerg C, Schwerk WB. Splenic infarction: sonographic patterns, diagnosis, follow-up, and complications. Radiology 1990; 174:803-807. 19. Ginel PJ, Lucena R, Arola J, et al. Diffuse splenomegaly caused by splenic abscessation in a dog. Vet Rec 2001; 149:327-329. 20. Hanson JA, Penninck DG. Ultrasonography evaluation of a traumatic splenic hematoma and literature review. Vet Radiol Ultrasound. 1994; 35(6):463-468. 21. Lupien C, Sauerbrei EE. Healing in the traumatized spleen: sonographic investigation. Radiology 1984; 151:181-185.

28. Sato AF, Solano M. Ultrasonographic findings in abdominal mast cell disease: a retrospective study of 19 patients. Vet Radiol Ultrasound 2004; 45:51-57. 29. Book AP, Fidel J, Wills T, et al. Correlation of ultrasound findings, liver and spleen cytology, and prognosis in the clinical staging of high metastatic risk canine mast cell tumors. Vet Radiol Ultrasound 2011; 52(5):548-554. 30. Hickford FH, Stokol T, vanGessel YA, et al. Monoclonal immunoglobulin G cryoglobulinemia and multiple myeloma in a domestic shorthair cat. JAVMA 2000; 217:1029-1033, 1007-1028. 31. Saunders HM, Neath PJ, Brockman DJ. B-mode and Doppler ultrasound imaging of the spleen with canine splenic torsion: A retrospective evaluation. Vet Radiol Ultrasound 1988; 39:349–353. 32. Gaschen L, Kircher P, Venzin C, Hurter K, Lang J. Imaging diagnosis: The abdominal air-vasculogram in a dog with splenic torsion and clostridial infection. Vet Radiol Ultrasound 2003; 44:553–555. 33. Stefanello D, Valenti P, Faverzani S, et al. Ultrasound-guided cytology of spleen and liver: a prognostic tool in canine cutaneous mast cell tumor. J Vet Intern Med 2009; 23(5):1051-1057.

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NAVC PERSPECTIVES NAVC PERSPECTIVES continued from page 11

that will hone practitioners’ skills in a stimulating setting with other motivated professionals. Three in-depth courses will be offered between the two locations, including Soft Tissue Surgery, Small Animal Ultrasound, and Fear Free. And of course, the NAVC is also coordinating with Visit Buffalo/Niagara to include fun excursions on the itinerary! NAVC Live: Portland (Portland, Oregon; August 20-23, 2017) This year, the NAVC will launch a new event in Portland, Oregon, featuring an immersive learning-focused experience. Open to all veterinary professionals, NAVC Live will take place at the Hilton Portland & Executive Tower and offer the same great continuing education the NAVC always provides. Portland itself offers limitless recreation, fabulous food and drink, and a flourishing culture where something’s always happening.

SEE YOU SOON! So here’s to the NAVC doing what we do best… becoming bigger, better, and more creative in the ways we serve an ever-changing and expanding industry. We look forward to bringing you more opportunities for education, growth, and, of course, our unique brand of inspiration.

—Thomas M. Bohn, CAE, NAVC Chief Executive Officer, VIC Board Chair

The Conference Exhibit Hall is a great way to connect with industry leaders and learn more about innovative and creative resources to make your practice better.

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NAVC INSTITUTE 2017 Master today’s most cutting-edge techniques through total immersion skills training.

2017 Courses: • ABVP Examination Preparation Sponsored by:

Sponsored by:

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• Small Animal Ultrasound (Group 2)

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DERMATOLOGY DETAILS

Dermatology Diagnostics: Cutaneous Cytology Chris Reeder, DVM, DACVD BluePearl Veterinary Partners, Franklin, Tennessee shutterstock.com/Komsan Loonprom

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Cytology is one of the most important yet commonly underused tools in veterinary medicine. It is a quick, easy, and inexpensive means of gathering a tremendous amount of diagnostic information, much the same as running fecal floats, blood smears, and serum chemistries/complete blood counts. According to Christopher et al in the Journal of the American Veterinary Medical Association, “Cutaneous/ subcutaneous cytology are most accurate for diagnosis of lesions, whereas liver cytology is least accurate.”1 Moreover, Ruocco et al report that “Exfoliative cytology for diagnostic purposes is rarely used in dermatology despite the rapid and reliable results which this procedure can offer in many clinical conditions.”2 Knowing how to take cytologic samples and how to interpret those samples can be critical to an animal’s health, disease management, and overall wellbeing.

disease, the degree of stenosis may make insertion of the applicator into the ear canal impossible. A 5-French red rubber catheter may be used to obtain samples from more stenotic ear canals. If a dog has a patent ear canal with a ruptured or absent tympanic membrane, sampling of the middle ear may be possible. In these cases, a red rubber or tomcat catheter can be used to obtain the sample while the patient is under general anesthesia. If the tympanic membrane is intact, a myringotomy using a spinal needle will be required. Specific techniques on myringotomy may be found in Mueller and Kirk’s Small Animal Dermatology, 7th edition.

OBTAINING SAMPLES Ear Canal

• Roll this material onto a glass slide. I like to write “R” for right and “L” for left on the slide to identify the side from which each sample was obtained (Figure 1).

The best method for obtaining material from the ear is with a cotton-tipped applicator; however, the health of the ear may limit access to sampling sites. For example, if a dog has end-stage proliferative ear

Griffin et al found that heat fixing versus not heat fixing otic exudate on glass slides before staining did not increase or decrease the number of Malassezia yeast organisms found on cytologic

DERMATOLOGY DETAILS

• Try to obtain a sample at the junction of the vertical and horizontal canals. This is approximately the farthest it is possible to see into the ear without an otoscope.

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evaluation.3 I prefer the slide to be heat fixed, then stained with a quick stain (eg, DiffQuik).

Claw Skin Folds Two methods exist for taking samples from claw folds (cuticle areas):

• Using the edge of a glass slide to obtain the debris (usually a waxy substance) by scraping from distal to proximal in a scooping motion at a 30° to 45° angle. • Using a cotton-tipped applicator broken in half. The stick portion should have a beveled edge. Use the beveled edge to gently scrape or extract

material from around the proximal claw/claw skin folds and rub it onto a glass slide (Figure 2). This method may be preferable to using a glass slide directly in these areas, which can be challenging and could result in the slide breaking. The amount of material/debris will be very small. The slide should be heat fixed and a quick stain used for preparation.

Skin Surface In my experience, skin cytology is the diagnostic test most commonly missed in everyday referral cases. I find direct impression smears to be most rewarding.

• Obtain a sample by scraping the skin with the edge of a glass slide at a 30° to 45° angle (Figure 3). This technique is useful for the paws, ventrum, pustules, papules, facial folds, and other areas. FIGURE 1. Ear cytology: Right and left markers.

• Consider tape preps, which tend to be more useful in areas that are very dry or difficult to access with a slide, such as interdigital spaces, facial or tail folds, and periocular areas. −− Using a clear, cellophane-type tape, press the sticky portion directly onto the area of interest. −− Stain the sample only by using the stain and counterstain (red and purple), then affix the tape directly to a glass slide for evaluation. −− Note that fixative will remove the sticky portion along with the sample.

INTERPRETING CYTOLOGIC RESULTS Basic Microscopy Always start at low power! The most common mistake made in viewing cytologic preparations is going directly to 100× magnification. Starting at 4× allows identification of specific areas of the slide for examination at higher powers. It also enables observation of findings that might be missed at 100×, such as acantholytic cells and Demodex mites (Figures 4 and 5).

FIGURE 2. Sampling claw folds.

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Inflammatory Cells Inflammatory cells are seen in almost all skin cytologic examinations and occasionally on ear canal and claw fold cytology. The presence of different inflammatory cells may be a guide to suspect certain diseases, such as pemphigus complex, cutaneous lupus, mucocutaneous pyoderma, or even allergies. Neutrophils

Neutrophils are acute inflammatory cells that destroy infectious organisms and are the main component of pus. Intracellular bacteria should be scanned for because the presence of these bacteria is the true definition of skin infection. The presence of numerous bacteria with no intracellular bacteria may be the result of immunosuppression (eg, Cushingâ&#x20AC;&#x2122;s disease, hypothyroidism, neoplasia)

FIGURE 4. Acantholytic cells.

FIGURE 3. Skin scraping.

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FIGURE 5. Demodex mite.

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or bacterial overgrowth. In light of current concerns about resistance to antimicrobial drugs, I recommend treating these cases topically with an antimicrobial product (eg, chlorhexidine, micronized silver, Triz EDTA) as the first step. Neutrophils release many proteolytic enzymes responsible for inflammation and tissue damage (Figure 6). Eosinophils

Eosinophils are filled with red (eosinophilic) granules (Figure 7). Eosinophils produce numerous cytokines and mediators to kill microorganisms and attract other cells, such as mast cells. These cells are also phagocytic and are capable of ingesting bacteria and fungi. Finding eosinophils on skin cytology suggests the presence of parasites, fungi, or food allergies. Eosinophils are rarely found in dogs with atopic dermatitis, although they are common in cats.

Lymphocytes

Lymphocytes are usually seen later in the course of skin disease and are not usually found in large numbers. Small, medium, and large lymphocytes may be seen. These cells direct activities of other cells (eg, neutrophils, eosinophils, keratinocytes) through the release of various messaging molecules, or cytokines. Large lymphocytes are sometimes seen in dogs with cutaneous lymphoma (Figure 8). Mast Cells

Mast cells are also found later in a disease process (Figure 9). They are the major producer of histamine and are involved to a large extent in allergic skin disease. Usually they are seen only in ulcerated areas of dermal mast cell tumors.

FIGURE 6. Neutrophils.

FIGURE 8. Atypical lymphocytes (consistent with cutaneous lymphoma).

FIGURE 7. Eosinophils.

FIGURE 9. Mast cell (center).

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Nuclear Streaming

Fungi

When cells rupture during sampling, nuclear content (DNA) is often seen on cytology. Nuclear streaming looks like fine threads of eosinophilic material (Figure 10). It does not indicate anything other than the rupturing of cells during sample collection. It can help to outline fungal spores, bacteria, and yeast, so look for these organisms in areas with larger amounts of nuclear streaming.

Fungal spores from dermatophytes (ringworm) can be seen within neutrophils, can be free, or can be present within nuclear streaming. These very small, round organisms have a clear halo and basophilic center (Figure 11). They are about half the size of an average red blood cell.

Parasites

Two genera of yeast are seen: Malassezia species are more common in the United States than Candida species, which tend to be more common in Europe. Malassezia species have been described as peanut-, snowman-, footprint-, or bowling pin– shaped basophilic organisms. These organisms are defined as a broad-based budding yeast.

Demodex, Otodectes, scabies, or other mites may be visible on cytologic preparations if the infection is severe enough. These are large organisms and are best evaluated with 4× to 10× magnification. They are not common but are of diagnostic value if seen.

Yeast

Bacteria

FIGURE 10. Nuclear streaming.

FIGURE 11. Fungal spores.

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Bacteria are the most common infectious organisms I find on cytologic examination. Two distinct shapes are most common: cocci and rods. Cocci are round, basophilic bacteria found individually, in clusters, or in large groups (Figure 10). If intracellular cocci are found, a true infection is present. Rods are often found individually or in sets of 2 placed end to end, called diploid rods (Figure 12). Cocci are most often Staphylococcus or Streptococcus species. Rods are often Escherichia coli, Pseudomonas species, or Klebsiella species. Remember, quick stains stain all bacteria

FIGURE 12. Rods with inflammatory cells.

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purple; they do not distinguish gram-positive from gram-negative bacteria. Bacterial cultures should be performed any time rods are seen on cytology. Bacteria always go in and out of focus when the fine focus on the microscope is used, whereas melanin granules have a refractory/reflective quality.

Chris Reeder

Chris Reeder, DVM, DACVD, is a graduate of Auburn University’s College of Veterinary Medicine and board-certified in veterinary dermatology. Dr. Reeder has published several articles both nationally and internationally and enjoys lecturing to local and national audiences on dermatology. He has served on several committees for the American College of Veterinary Dermatology, including the credentials committee and ad hoc exam committee. Dr. Reeder’s special interests include otitis externa, dermatopathology, and immune-mediated skin disease.

Melanin Granules Melanin granules are commonly mistaken for bacteria and are normally seen on pigmented areas of the skin. They are golden to brown in color and mostly rod-shaped; they have a refractive/reflective quality when going in and out of fine focus (Figure 13). Melanin granules are usually seen attached to keratinocytes, but they can be seen free on the slide.

Keratinocytes Most keratinocytes are octagonal to square and squamous in composition. Keratinocytes may display some interesting features that may be normal or abnormal, such as inclusion of keratohyaline granules or rounded acantholytic cells. Keratohyaline Granules

These granules are present in immature skin cells in the granular layer and are involved in “cementing” the cells together when fully mature. All species have these granules, which may be seen in keratinocytes that are chronically irritated (eg, in allergic dogs/cats). Keratohyaline granules are large eosinophilic granules. Dogs have round granules and cats have rod-shaped granules (similar to eosinophils; Figure 14).

FIGURE 13. Melanin granules.

Acantholytic Cells

These keratinocytes have lost their intercellular connections deeper in the epidermis and are usually found in animals with immune-mediated disease, such as pemphigus. Occasionally, severe bacterial infections and dermatophytosis can cause these cells to develop. Acantholytic cells are “fried egg”–shaped, with a deeply basophilic, centrally located nucleus (Figure 4). These are very important to recognize and are considered abnormal in any animal. References 1.

Christopher MM, Hotz CS, Shelly SM, Pion PD. Use of cytology as a diagnostic method in veterinary practice and assessment of communication between veterinary practitioners and veterinary clinical pathologists. JAVMA 2008; 232(5):747-754.

2. Ruocco E, Brunetti G, Vecchio M Del, Ruocco V. The practical use of cytology for diagnosis in dermatology. J Eur Acad Dermatol Venereol 2011; 25(2):125-129. 3. Griffin JS, Scott DW, Erb HN. Malassezia otitis externa in the dog: the effect of heat-fixing otic exudate for cytological analysis. J Vet Med 2007; 54(8):393-448.

FIGURE 14. Keratohyaline granules.

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TRESADERM (thiabendazole-dexamethasoneneomycin sulfate solution) Dermatologic Solution CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION: Dermatologic Solution (thiabendazole-dexamethasoneTRESADERM® neomycin sulfate solution) contains the following active ingredients per ml: 40 mg thiabendazole, 1 mg dexamethasone, 3.2 mg neomycin (from neomycin sulfate). Inactive ingredients: glycerin, propylene glycol, purified water, hypophosphorous acid, calcium hypophosphite; about 8.5% ethyl alcohol and about 0.5% benzyl alcohol. INDICATIONS:Dermatologic solution TRESADERM is indicated as an aid in the treatment of certain bacterial, mycotic, and inflammatory dermatoses and otitis externa in dogs and cats. Both acute and chronic forms of these skin disorders respond to treatment with TRESADERM. Many forms of dermatosis are caused by bacteria (chiefly Staphylococcus aureus, Proteus vulgaris and Pseudomonas aeruginosa). Moreover, these organisms often act as opportunistic or concurrent pathogens that may complicate already established mycotic skin disorders, or otoacariasis caused by Otodectes cynotis. The principal etiologic agents of dermatomycoses in dogs and cats are species of the genera Microsporum and Trichophyton. The efficacy of neomycin as an antibacterial agent, with activity against both gram-negative and gram-positive pathogens, is well documented. Detailed studies in various laboratories have verified the significant activity thiabendazole displays against the important dermatophytes. Dexamethasone, a synthetic adrenocorticoid steroid, inhibits the reaction of connective tissue to injury and suppresses the classic inflammatory manifestations of skin disease. The formulation for TRESADERM combines these several activities in a complementary form for control of the discomfort and direct treatment of dermatitis and otitis externa produced by the above-mentioned infectious agents. DOSAGE AND ADMINISTRATION: Prior to the administration of Dermatologic Solution TRESADERM, remove the ceruminous, purulent or foreign materials from the ear canal, as well as the crust which may be associated with dermatoses affecting other parts of the body. The design of the container nozzle safely allows partial insertion into the ear canal for ease of administration. The amount to apply and the frequency of treatment are dependent upon the severity and extent of the lesions. Five to 15 drops should be instilled in the ear twice daily. In treating dermatoses affecting other than the ear the surface of the lesions should be well moistened (2 to 4 drops per square inch) with Dermatologic Solution TRESADERM twice daily. The volume required will be dependent upon the size of the lesion. Application of TRESADERM should be limited to a period of not longer than one week. PRECAUTIONS: On rare occasions dogs may be sensitive to neomycin. In these animals, application of the drug will result in erythema of the treated area, which may last for 24 to 48 hours. Also, evidence of transient discomfort has been noted in some dogs when the drug was applied to fissured or denuded areas. The expression of pain may last 2 to 5 minutes. Application of Dermatologic Solution TRESADERM should be limited to periods not longer than one week. While systemic side effects are not likely with topically applied corticosteroids, such a possibility should be considered if use of the solution is extensive and prolonged. If signs of salt and water retention or potassium excretion are noticed (increased thirst, weakness, lethargy, oliguria, gastrointestinal disturbances or tachycardia), treatment should be discontinued and appropriate measures taken to correct the electrolyte and fluid imbalance. Store in a refrigerator 36°-46°F (2°-8°C). WARNING: For topical use in dogs and cats. Avoid contact with eyes. Keep this and all drugs out of the reach of children. The Material Safety Data Sheet (MSDS) contains more detailed occupational safety information. To report adverse effects in users, to obtain an MSDS, or for assistance call 1-888-637-4251. HOW SUPPLIED: Product 55871Dermatologic Solution TRESADERM Veterinary is supplied in 7.5-ml and 15-ml dropper bottles, each in 12-bottle boxes.

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Approved for use on dogs and cats IMPORTANT SAFETY INFORMATION: TRESADERM is for topical use only in dogs and cats. On rare occasions, application of the product may result in erythema or discomfort in the treated area. Discomfort in the treated area can last from 24 hours to 48 hours. Merial is now part of Boehringer Ingelheim. ®TRESADERM is a registered trademark of Merial. ©2017 Merial, Inc., Duluth, GA. All rights reserved. TRE15TRADEADD (03/17).

shutterstock.com/Helioscribe

HOW I TREAT

How I Treat… Separation Anxiety AN INTERVIEW WITH DR. TERRY CURTIS

Today’s Veterinary Practice “How I Treat” column is based on the popular How I Treat sessions presented at the annual NAVC Conference in Orlando, Florida (navc.com/conference). This column features interviews with leading veterinary specialists on pertinent clinical topics, with the goal of bringing practitioners essential information on therapeutic approaches.

In this How I Treat interview, Terry Curtis, DVM, MS, DACVB, answers our questions about key treatment protocols for behavior issues noted when the owner is leaving or not at home, often diagnosed as “separation anxiety.”

Q. What are the classic signs of separation anxiety in dogs that practitioners may recognize from an owner’s description of a dog’s behavior? A. Classic signs of panic in dogs include distress vocalization (howling, yelping), elimination (“fight or flight” urination and/or defecation), attempts at escape that result in destruction (typically

Terry Curtis, DVM, MS, DACVB University of Florida College of Veterinary Medicine

through the door by which their owners have left), and/or destruction of other locations or objects (digging at walls, chewing at furniture, etc). Dogs that feel panic at being left alone typically do so for 3 reasons: 1. They are anxious at watching their owners leave (departure anxiety). 2. They are anxious if they find themselves alone (separation anxiety). 3. They are alone in a crate or other enclosure (crate/barrier anxiety). MARCH/APRIL 2017

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Any of these can be discrete presentations, or they can be seen in combination. Dogs with departure anxiety tend to show anxiety when they observe their owners’ “pre-departure” signals: putting on certain clothes and shoes, packing a briefcase or handbag, picking up keys, etc. These dogs have learned—through classical conditioning—to associate these actions with being left behind.

Veraflox (pradofloxacin) Oral Suspension for Cats 25 mg/mL For the treatment of skin infections (wounds and abscesses) in cats. Do not use in dogs. BRIEF SUMMARY: Before using Veraflox Oral Suspension for Cats, please consult the product insert, a summary of which follows: CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. Federal law prohibits the extra-label use of this drug in food-producing animals. PRODUCT DESCRIPTION: Pradofloxacin is a fluoroquinolone antibiotic and belongs to the class of quinolone carboxylic acid derivatives. Each mL of Veraflox Oral Suspension provides 25 mg of pradofloxacin. INDICATIONS: Veraflox is indicated for the treatment of skin infections (wound and abscesses) in cats caused by susceptible strains of Pasteurella multocida, Streptococcus canis, Staphylococcus aureus, Staphylococcus felis, and Staphylococcus pseudintermedius. CONTRAINDICATIONS: DO NOT USE IN DOGS. Pradofloxacin has been shown to cause bone marrow suppression in dogs. Dogs may be particularly sensitive to this effect, potentially resulting in severe thrombocytopenia and neutropenia. Quinolone-class drugs have been shown to cause arthropathy in immature animals of most species tested, the dog being particularly sensitive to this side effect. Pradofloxacin is contraindicated in cats with a known hypersensitivity to quinolones. HUMAN WARNINGS: Not for human use. Keep out of reach of children. Individuals with a history of quinolone hypersensitivity should avoid this product. Avoid contact with eyes and skin. In case of ocular contact, immediately flush eyes with copious amounts of water. In case of dermal contact, wash skin with soap and water for at least 20 seconds. Consult a physician if irritation persists following ocular or dermal exposure or in case of accidental ingestion. In humans, there is a risk of photosensitization within a few hours after exposure to quinolones. If excessive accidental exposure occurs, avoid direct sunlight. Do not eat, drink or smoke while handling this product. For customer service or to obtain product information, including a Material Safety Data Sheet, call 1-800633-3796. For medical emergencies or to report adverse reactions, call 1-800-422-9874. ANIMAL WARNINGS: For use in cats only. The administration of pradofloxacin for longer than 7 days induced reversible leukocyte, neutrophil, and lymphocyte decreases in healthy, 12-week-old kittens. PRECAUTIONS: The use of fluoroquinolones in cats has been associated with the development of retinopathy and/or blindness. Such products should be used with caution in cats. Quinolones have been shown to produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. The safety of pradofloxacin in cats younger than 12 weeks of age has not been evaluated. The safety of pradofloxacin in immune-compromised cats (i.e., cats infected with feline leukemia virus and/or feline immunedeficiency virus) has not been evaluated. Quinolones should be used with caution in animals with known or suspected central nervous system (CNS) disorders. In such animals, quinolones have, in rare instances, been associated with CNS stimulation that may lead to convulsive seizures. The safety of pradofloxacin in cats that are used for breeding or that are pregnant and/or lactating has not been evaluated. ADVERSE REACTIONS: In a multi-site field study, the most common adverse reactions seen in cats treated with Veraflox were diarrhea/loose stools, leukocytosis with neutrophilia, elevated CPK levels, and sneezing. ANIMAL SAFETY: In a target animal safety study in 32, 12-week-old kittens dosed at 0, 1, 3, and 5 times the recommended dose for 21 consecutive days. One 3X cat and three 5X cats had absolute neutrophil counts below the reference range. The most frequent abnormal clinical finding was soft feces. While this was seen in both treatment and control groups, it was observed more frequently in the 3X and 5X kittens.

Dogs with separation anxiety are those that panic as soon as they realize they are alone. This can be shortly after their owners leave the house (typically within just a few minutes). Dogs with separation anxiety can also panic when their owners are home but not within sight—such as out in the yard, in another room, or in the shower. Dogs with crate/barrier anxiety are those that panic because they are confined. These dogs typically present for breaking out of crates and, often, injuring themselves (broken teeth, torn claws, or ulcerated muzzles).

Q. What investigative measures would you advise to rule out other causes of these behaviors? A. A dog with crate/barrier anxiety is the easiest to confirm and treat. To do so, simply leave the dog out of the crate. Many of these dogs were crated as puppies because they were thought to have “separation anxiety,” perhaps because they eliminated in the house as a result of incomplete house training. Once the barrier is removed, this group of dogs is no longer anxious when left alone. To confirm the other two types, because the behavior that we need to observe is happening out of the owner’s sight, it is important to video the behavior. Once there is a record of the dog’s activity when alone, we have more information as to the correct diagnosis and treatment plan. For example, if the dog is seen pacing, panting, urinating, and defecating just minutes after the owner leaves—that’s panic. However, if the dog urinates by the door 3 hours after the owner has left, this behavior could be “I gotta go!” It is then a matter of the dog not being completely housebroken.

U.S Patent No. 6,323,213 May, 2012 84364593/84364607, R.0 NADA141-344, Approved by FDA Made in Germany Bayer, the Bayer Cross and Veraflox are registered trademarks of Bayer. 17928 Bayer HealthCare LLC BAY022614 Animal Health Division Shawnee Mission, Kansas 66201, U.S.A.

41411_Veraflox_Label_TODAYS VET_FA.indd 1

Getting a complete history from the client is extremely important. For example, concerning the destructive dog, one should ask, “What items are being destroyed?” Again, if the video shows the dog furiously digging at the door that leads out to the garage—the owner’s departure door—then that points

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CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. Federal law prohibits the extra label use of this drug in food-producing animals. WARNING: For use in cats only. PRECAUTION: The safety of pradofloxacin in cats younger than 12 weeks of age has not been evaluated. *The clinical significance of in vitro data has not been demonstrated. † Veraflox® is indicated for the treatment of skin infections (wounds and abscesses) in cats caused by susceptible strains of Pasteurella multocida, Streptococcus canis, Staphylococcus aureus, Staphylococcus felis, and Staphylococcus pseudintermedius. Silley P, Stephan B, Greife H, Pridmore A. (2012). Bactericidal properties of pradofloxacin against veterinary pathogens. Vet Microbiol. 157(2012): 106-111. Freedom of Information Summary: NADA 141-344.

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HOW I TREAT

to a diagnosis of departure/separation anxiety. However, if the dog is seen scanning the kitchen counters and garbage cans for goodies, then we’re dealing with an entirely different problem. Remember to consider when the behavior occurs. If the dog is okay for Monday, Wednesday, Thursday, and Friday departures but “goes berserk” on Tuesdays— what’s different? It may be that Tuesday is trash pick-up day, or the day when the pool people come. If the behavior is even more random, the owner should keep a log of when the dog exhibits the anxious behavior. Did the dog’s excessive salivation coincide with a storm? Did the dog damage the blinds because of a package delivery? Often, it is not until we start looking for a pattern that we find one.

Q. How can an owner improve separation-related behavior? A. As mentioned, for dogs that have distress only when crated or enclosed in a small space, treatment can be very simple and straightforward: let the dog out of the crate or small space. Owners of dogs that have learned that departures or being alone is scary have more homework to do. Often, departure and separation anxiety are seen together, so the following recommendations are indicated for both presentations. First, owners need to address the actions and cues that predict their departure. This can be done several ways:

• Get rid of the cues. For example, briefcases can be packed and put into the car the night before, or the car can be pulled out of the garage hours before departure so

• Habituate the dog to cues. This is done by the owners repeating actions over and over—but not leaving. For example, owners can pick up their keys and walk around the house. Then maybe they pick up their keys, go into the kitchen, and cook dinner. Perhaps they pick up their keys, sit down, and read a book. Over time, the dog will no longer react to the sound of the keys, because it no longer has a predictive quality. During this time, for actual departures, the keys would need to be put into a pocket or bag so the dog doesn’t hear the sound as the owner leaves. • Use classical conditioning for good! Owners can turn a negative action (such as putting on certain shoes) into a positive one by pairing it with a special treat. So, instead of “See dad putting on loafers and panic because he’s leaving!” it becomes “See dad putting on loafers and look for a yummy treat!” Once the cues are no longer predictive of a departure, owners can start leaving for longer and longer periods of time, which teaches the dog that it can be alone. For some dogs, the panic is so severe that other options need to be employed, such as dog-sitters or doggie daycare.

Q. What medications can be used to assist with behavioral modification, and how successful are they? A. Medications used to decrease anxiety and panic can be very helpful in the treatment of separation-related behaviors. Generally, there are two groups of medications to consider: • Long-term, daily-administered medications

Age Matters

• As-needed medications for departures only

One should take into account the dog’s age when considering a diagnosis. It is important to rule out “normal” puppy behavior: destruction, elimination, etc. Conversely, in an older dog, one should consider the possibility of cognitive decline, especially if it is a recent behavioral change.

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there is no longer the predictive sound of the garage door going up and down.

Currently, Clomicalm (clomipramine) is the only FDA-approved medication for the treatment of separation anxiety in dogs. It is a tricyclic antidepressant (TCA) that targets the serotonin system. Other, more common medications that positively affect serotonin are fluoxetine (Prozac) and paroxetine (Paxil), which are selective serotonin HOW I TREAT

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“ NVA didn’t come in and redo our practice. For the nine years before we

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HOW I TREAT

reuptake inhibitors (SSRIs). All of these medications are given daily and generally take several weeks to reach peak effects. These medications should never be given together, because serotonin syndrome could result. The benzodiazepines and trazodone are fast-acting and short-acting medications and can therefore be very helpful in addressing the panic that dogs feel. These medications can be used alone or in combination with a TCA or an SSRI. Antianxiety alternatives such as pheromones, supplements, and diets can also be used alone or in combination with one or more of the medications discussed here.

Terry Marie Curtis

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Terry Marie Curtis, DVM, MS, DACVB, graduated with honors from the University of Florida (UF) College of Veterinary Medicine and worked as a feline-only practitioner before starting her residency in veterinary behavior at the University of Georgia in 2001. Concurrently, she received a master of science degree in psychology, investigating grooming behavior in the domestic cat. Dr. Curtis currently does house calls in Florida and South Georgia and teaches 2 behavior courses at the UF College of Veterinary Medicine. In addition to being a regular contributor to the NAVC Conference and an author of numerous articles and book chapters, she is a member of the Editorial Review Board for Today’s Veterinary Practice and the Journal of Feline Medicine & Surgery. She was also a panel contributor to the 2014 AAFP & ISFM Guidelines for Diagnosing and Solving House Soiling Behavior in Cats.

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P O R T L A N D ,

O R E G O N

AUGUST 20-23 , 2017 T H E HILTON P ORTLA N D & EX EC U T I V E TOW ER The NAVC is extending its popular educational platform to the great Northwest with an innovative experience unlike any conference you’ve seen before. NAVC LIVE will feature professional “case theater” veterinarian/client presentations, live-streamed general sessions, short talks, Q&A for remote attendees and clinical content in a non-clinical setting, as well as engaging networking opportunities, key tours and experiences in one of the West Coast’s hottest travel destinations. FEATURED EDUCATIONAL TRACKS AND COURSE LEADERS: • Ain’t Doin’ Right: Approaches to the Clinically Vague: Christopher Byers, DVM, DACVECC, DACVIM (SAIM), CVJ

• Behavior: Karen Overall, BA, MA, VMD, PhD, DACVB • Cardiology: Andrea Ericksson De Rezende, DVM, DACVIM (Cardiology) • Dermatology: Dunbar Gram, DVM, DACVD • Endocrinology: Christopher Byers, DVM, DACVECC, DACVIM (SAIM), CVJ • Oncology: Sue Ettinger, DVM, DACVIM (Oncology) • Ophthalmology: Caryn Plummer, DVM, DACVO • Pursuit of Happiness: Practice Challenges, Conflict Management and Wellbeing in Veterinary Medicine: Mary Gardner, DVM & Andrew Roark, DVM, MS

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FOCUS ON PHARMACOLOGY

Use of Antibiotics for the Urinary Tract JD Foster, VMD, DACVIM, Friendship Hospital for Animals, Washington, DC

shutterstock.com/Elenica

Urinary tract infections (UTIs) are common in small animal practice; it has been reported that up to 27% of dogs will develop infection at some time in their lives.1 Most UTIs are successfully treated with commonly used drugs, dosages, and administration intervals. However, infections can be challenging to effectively treat when they involve the kidneys (pyelonephritis) and prostate (prostatitis). In addition, it can be difficult to create an appropriate antibiotic prescription in patients with kidney disease due to reduced drug clearance. Understanding drug pharmacokinetics (PK) and pharmacodynamics (PD) is essential when determining the most effective antibiotic therapy. In addition, successful antimicrobial therapy requires appropriate choice of antibiotic, including dose, frequency, and duration (Figure 1).

PATHOPHYSIOLOGY OF UTI Nearly all infections are caused by pathogenic bacteria, although fungal or viral UTIs may be rarely encountered. Most bacterial lower UTIs

result from bacteria ascending the external genitalia and urethra. Less commonly, bacteria travel hematogenously and colonize the urinary tract. Numerous innate defense mechanisms help prevent a UTI. Complete and regular voiding, along with intrinsic properties of urine (high osmolality, antimicrobial solutes), helps create a hostile environment for microbes within the urinary tract. Anatomic barriers and mucosal defenses further prevent adherence of virulent bacteria to the urothelium. Pathogenic bacteria increase the permeability of the urothelium, allowing passage of inflammatory solutes

Signs of UTI • Dysuria • Hematuria • Pollakiuria • Stranguria

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Determine type of UTI based on clinical signs, patient examination, blood analysis, urinalysis, imaging, etc.

Urine culture and susceptibility report

Select dosage of drug to deliver appropriate blood or urine concentration

Select dosing interval to meet targets

Time dependent: concentration > MIC for 50%–75% of dosing interval

Concentration dependent: Peak drug concentration 8×–10× MIC

Uncomplicated UTI

Complicated UTI

Recurrent UTI

7 days of therapy

4 weeks of therapy

4 weeks of therapy, treat underlying risk factors

FIGURE 1. Algorithm that provides guidance on appropriate selection of an antibiotic for urinary tract infection. MIC = minimum inhibitory concentration; UTI = urinary tract infection

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into the subepithelium as well as inflammatory cytokine secretion.2 The result is inflammation and pain, which manifest as dysuria, pollakiuria, stranguria, and/or hematuria. Eradication of the virulent organism can allow the normal permeability and integrity of the urothelium to be restored.

CLASSIFICATION OF UTI There are several classifications of UTI: Uncomplicated UTI is a sporadic bacterial cystitis found in a healthy patient with normal urinary tract anatomy and function.3 Complicated UTI occurs in a patient with functional or anatomic abnormalities of the urinary tract, or in patients with risk factors for persistent or recurrent infection as well as treatment failure. Such conditions include immunosuppression (due to natural disease or prescribed therapy), diabetes mellitus, hyperadrenocorticism, kidney disease,

prostatitis, pregnancy, urinary incontinence, and altered neurogenic function of the bladder.4 Recurrent UTI requires investigation to determine whether it is reinfection, relapsing, or refractory.

Reinfection is the return of a UTI—caused by a different organism—within 6 months of discontinuation of antibiotic therapy. Relapsing UTI occurs when the same organism is cultured again within 6 months of discontinuation of antibiotic therapy. This suggests that the patient has a condition that allows recolonization or one that prevents total eradication of infection; additional diagnostics are warranted in these patients (Table 1). Refractory UTI occurs when a positive urine culture is obtained during appropriate antibiotic therapy (based on in vitro susceptibility testing). There are several possible causes for refractory UTI, including:

• Decreased renal drug elimination (results in lower than expected urine drug concentration)

TABLE 1 Relapsing Urinary Tract Infections: Causes & Diagnostics CAUSES

Functional or structural abnormalities of the urinary tract that allow for recolonization of bacteria, including: • Urinary or fecal incontinence • Recessed vulva • Incomplete bladder emptying • Vaginal urine pooling Internal nidus that bacteria can colonize, preventing complete eradication, such as: • Neoplasia • Uroliths • Foreign material Altered immune function that creates difficulty in curing UTI, particularly when bacteriostatic drugs are used as therapy; such conditions include: • Hyperadrenocorticism • Diabetes mellitus • Systemic or local neoplasia •A dministration of immunosuppressive drugs and chemotherapy DIAGNOSTICS

• Abdominal ultrasonography • Computed tomography • Cystoscopy • Endocrine testing • Thoracic radiography • Urinary contrast study

CLSI Classification Isolate classifications—susceptible, intermediate, or resistant—are established by the Clinical Laboratory Standards Institute (CLSI) on the basis of drug PK and PD data. Several factors are considered in the establishment of CLSI breakpoint classifications. The peak drug concentration (Cmax) obtained by a standard dose and normal route of administration must be higher than the isolate’s minimum inhibitory concentration (MIC) for the isolate to be labeled susceptible. The Cmax is not always based on the drug concentration in urine. Some drugs have established CLSI breakpoints for UTI in some bacterial species (see CLSI publication VET01S); other breakpoints are based on infection in other organ systems or are even extrapolated from human use. Drugs for which no breakpoint has been determined for UTI may still be effective against “intermediate” organisms because the concentration of the drug in urine may be higher than in plasma. When urine culture and susceptibility results are used to choose appropriate therapy for pyelonephritis, the plasma breakpoints should be used, rather than urine breakpoints. 3 All of the preceding factors should be considered in selecting the most appropriate drug, as well as dosage and frequency of administration.

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• Inappropriate drug dose or administration schedule • Low drug bioavailability (eg, due to drug compounding or gastrointestinal disease) • Poor drug compliance Additionally, some drugs may show efficacy in vitro, but, for unknown reasons, the same effect is not present in vivo.

DIAGNOSTICS & DATA FOR ANTIBIOTIC SELECTION Pharmacokinetics & Pharmacodynamics PK is the movement of a drug throughout the body and includes absorption, distribution, metabolism, and excretion. PD is the effect of the drug on the body; in the case of antibiotics, this also includes the effect on the microorganism. These relationships, often referred to as PK/PD, help predict the outcome of any drug prescription. Alterations in PK may happen with abnormal absorption (eg, severe gastrointestinal disease), drug metabolism (eg, synthetic liver dysfunction), altered protein binding (eg, uremia, hypoproteinemia), and diminished drug excretion (hepatic or kidney failure). An antibiotic’s PD is assessed clinically through in vitro culture and susceptibility testing.

Culture & Sensitivity Ideally, all patients with a suspected UTI should have a urine sample collected via cystocentesis and evaluated by aerobic culture and antibiotic susceptibility testing. Urine culture is considered the gold standard in the diagnosis of UTI. The 2 techniques for determining antibiotic susceptibility are the disk diffusion and serial dilution methods. Disk diffusion testing is considered less reliable and does not provide the minimum inhibitory concentration (MIC) of the antibiotic, whereas antimicrobial dilution does provide the MIC and is the preferred method of antibiotic susceptibility testing.

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With antimicrobial dilution, a concentration of an antibiotic is added to a liquid medium inoculated with the bacterial isolate. The concentration of antibiotic is doubled in each subsequent well. The MIC is the concentration of antibiotic found in the first tube that exhibits no detectable growth,5 and this concentration is used to categorize the isolate as susceptible, intermediate, or resistant (see CLSI Classification). Rarely, false-negative findings may result from inappropriate urine storage or slow organism growth (as seen with Corynebacterium species). Urine processing for quantitative culture should be performed immediately after urine is obtained because bacterial colony count dramatically drops after 24 hours of refrigerated storage when urine is stored in a silicone clot tube.6 If urine cannot be processed for quantitative culture immediately, use of a urine transport tube is recommended to help prevent false-negative or underestimated colony count results.

Urine Drug Concentration Many antibiotics are excreted primarily in urine and achieve concentrations substantially higher than those in plasma. The urine drug concentration should be evaluated with respect to the isolate’s MIC to determine the likelihood of eliminating the organism. Table 2 lists observed urine concentration of antibiotics at the specified dosages in healthy animals. Urine antibiotic concentrations in veterinary patients with kidney disease have yet to be investigated. Reduced glomerular filtration rate (GFR) may decrease the excretion of the drug into urine, resulting in decreased urine concentrations. Additionally, polyuric patients may experience further reduction of urine drug concentration because of increased daily urine volume and subsequent dilution of filtered antibiotic. Decreased urine excretion caused by diminished GFR can result in plasma drug concentrations exceeding those normally observed and may cause adverse effects. This is most true for drugs with significant kidney elimination. Drugs with mostly

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hepatic elimination may have minimal alteration in drug excretion in patients with decreased GFR. However, the accumulated uremic toxins and hypoproteinemia present in many patients with kidney disease can lead to altered drug protein binding and abnormal drug PK/PD.

ANTIBIOTIC SELECTION BY UTI CLASSIFICATION Empiric Antibiotic Selection The emergence of antimicrobial resistance and multidrug resistance has increased, making empiric antibiotic selection very difficult, particularly when previous antibiotic therapy has been administered to the patient.4

Uncomplicated UTI Recommended drugs for uncomplicated UTI include amoxicillin, cephalosporins, and trimethoprim-sulfonamide.3,6 Although patients with an uncomplicated UTI are often successfully treated empirically, repeated treatment without culture and susceptibility results may lead to incorrect choice of antimicrobial, unnecessary adverse effects, and potential selection of resistant bacteria.4

Complicated & Recurrent UTI Antibiotics should never be selected empirically for complicated UTI without culture susceptibility results (see Culture & Sensitivity). Management of pyelonephritis, prostatitis, and relapsing or recurrent

TABLE 2 Antibiotics for Urinary Tract Infections, including Mean Urine Drug Concentrations7-9 DRUG

DOSAGE & ROUTE

MEAN URINE CONCENTRATION (MCG/ML)

Amikacin

5 mg/kg SC q24h

342 ± 143

Amoxicillin

11 mg/kg PO q8h

202 ± 93

12.5 mg/kg PO q8h

201

Ampicillin

26 mg/kg PO q8h

309 ± 55

Cefovecin

8 mg/kg SC q15d

9 ± 6.5 (12 h post) 0.9 ± 0.7 (15 d post) 66 ± 37 (12 h post) 3 ± 1.6 (15 d post)

Cephalexin

18 mg/kg PO 30 mg/kg PO q8h

500 225

Chloramphenicol

35 mg/kg PO q8h

124 ± 40

Doxycycline

5 mg/kg PO q12h

53 ± 24

Enrofloxacin

5 mg/kg PO q24h

40 ± 10

2.75 mg/kg PO

Meropenem

20 mg/kg IV or SC

1296

Nitrofurantoin

4.4 mg/kg PO q8h

100

Sulfisoxazole

22 mg/kg PO q8h

1466 ± 832

Tetracycline

18 mg/kg PO q8h 20 mg/kg PO q8h

139 ± 65 145 ± 39

Trimethoprim/sulfadiazine

15 mg/kg PO q12h

55 ± 19

Amoxicillin/clavulanate

Marbofloxacin

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Antibiotics for Prostatitis The protein binding and lipid solubility of an antibiotic help determine its volume of distribution. Highly lipophilic drugs cross cell membranes and enter tissues easily. Such drugs are most effective in treating prostatitis, in which the blood–prostate barrier prevents passage of many water-soluble antibiotics (such as beta-lactams). In early stages of prostatitis, the blood–prostate barrier may be compromised, allowing delivery of water-soluble antibiotics to the site of infection. However, after the initial inflammation resolves (1–2 weeks, based on my clinical experience), this barrier is restored and these antibiotics may no longer reach effective tissue concentration within the prostate, preventing bacterial cure. The lipophilic drugs that achieve effective concentrations within the prostate include fluoroquinolones, sulfonamides, and macrolides; however, choice of antibiotic should be based on urine culture and susceptibility results.

UTI is often unsuccessful without therapy guided by culture and susceptibility results. However, therapy should be instituted while culture and susceptibility results are being awaited. Rational initial drug choices for complicated UTI include amoxicillin, fluoroquinolones, or trimethoprim-sulfonamide.3

ANTIBIOTIC SELECTION BY URINE DRUG CONCENTRATION To best use antibiotic urine data, an important consideration is whether a drug is time- or concentration-dependent.

Time-Dependent Drugs Time-dependent drugs include beta-lactams, cephalosporins, sulfa drugs, tetracyclines, and chloramphenicol. These drug classes are most effective when the tissue concentration exceeds the isolate’s MIC for 50% to 75% of the dosing interval.10 However, few clinical trials have evaluated this suggestion.11 Product inserts and pharmacology texts often contain the drug elimination curves, which are helpful in choosing the dosage and frequency that ensure these criteria are met. The plasma

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drug elimination curve and renal drug elimination rate can be used as surrogates to predict the urine drug concentration curve.12 Less is known about urine drug concentration and clinical efficacy, but several authors have stated that urine, not plasma, drug concentration is important in ensuring successful eradication of bacteria (see Urine Drug Concentration & Clinical Efficacy).7,9,12

Concentration-Dependent Antibiotics The efficacy of concentration-dependent antibiotics is best predicted by the Cmax and the isolate’s MIC. Such drugs as fluoroquinolones and aminoglycosides are most effective when the Cmax is at least 8- to 10-fold higher than the MIC.13 These drugs are typically administered every 24 hours. Another method to evaluate the activity of these antibiotics is comparing the drug concentration area under the curve (AUC) to the MIC. This AUC/MIC ratio has been investigated for some antibiotics, and although some authors generally recommend an AUC/MIC greater than 125 to 250, studies have shown some drugs to be effective with an AUC/MIC of 40.7,14,15 The dosage of these antibiotics is typically chosen to create a high peak urine concentration, well above the isolate’s MIC. Once-daily administration is acceptable for most concentration-dependent drugs, and this frequency may help increase owner compliance in administering medications. However, it may not be consistent with antibiotic stewardship to prescribe a fluoroquinolone antibiotic for an uncomplicated lower UTI when drugs belonging to the penicillin or cephalosporin class would also be effective.

DURATION OF THERAPY The ideal duration of antibiotic therapy for uncomplicated and complicated UTI is unknown. Many textbooks recommend 10 to 14 days for uncomplicated UTI and 4 to 8 weeks for complicated UTI; however, these guidelines are

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not evidence-based, and much shorter durations are the standard of care in human medicine. In 2011, the International Society for Companion Animal Infectious Diseases published recommendations regarding antimicrobial therapy in UTI.3 The recommendations mostly reflect expert consensus because well-designed clinical trials to determine optimal antibiotic duration are lacking in veterinary medicine.

• For uncomplicated UTI, this group recommended 7 or fewer days of antibiotic therapy; humans are typically treated for 3 to 7 days. • For complicated UTI, the group recommended antibiotic therapy for up to 4 weeks; humans are typically treated for 1 to 2 weeks, although 3 weeks may be indicated in some instances. Recently, 2 studies evaluated short duration versus long duration of antibiotics for uncomplicated UTI in dogs (3 days of trimethoprim-sulfamethoxazole versus 10 days of cephalexin and 3 days of enrofloxacin versus 14 days of amoxicillin-clavulanic acid).17,18 Both studies demonstrated that the short duration of antibiotic administration was noninferior to the longer duration in bacterial cure rates. However, because both studies compared short duration of one drug with long duration of another, their design precludes determination of optimal treatment time for the drugs investigated.19 A systematic literature review conducted in 2015 to determine the optimal therapy for UTI in veterinary medicine found insufficient evidence available for analysis.19 Currently, evidence-based guidelines for the duration of UTI in small animals do not exist, and further studies evaluating a single drug in both short and long durations of therapy are needed.

MONITORING RESPONSE TO THERAPY Patients with a simple, uncomplicated UTI may not require rigorous monitoring. However, patients with complicated, relapsing, or recurrent infections should be monitored very closely. The following protocol is recommended to monitor response to therapy in patients with relapsing, recurrent, or refractory UTI.3

Urine Drug Concentration & Clinical Efficacy Antimicrobial drugs must achieve an adequate urine concentration, which must be maintained for a sufficient time for a drug to be effective in treating UTI.16 It has been suggested that clinical efficacy is observed when the urine drug concentration is maintained at a concentration 4-fold higher than the isolate’s MIC throughout the time between doses. 9 Experimental studies in rats have shown that the time for which the plasma drug concentration exceeds the isolate’s MIC correlates to the magnitude of bacterial colony count reduction; the longer the time for which the drug concentration remained above the MIC, the lower the urine colony counts.12 Successful eradication of bacteria within the renal parenchyma or urinary bladder wall is correlated to the plasma, not urine, drug concentration. When prescribing time-dependent antibiotics, shortening the interval between drug administration is the most effective method to allow the tissue/urine drug concentration to exceed the MIC for the majority of the dosing interval. •D rug elimination follows first-order kinetics, where 50% of the drug is lost in 1 half-life. • I n contrast, doubling the dose would only add 1 half-life to the dosing interval. •T o add 2 half-lives to the dosing interval, the initial dose would have to be increased 4-fold. The peak serum drug concentration achieved by this approach may exceed the window of safety, producing adverse drug effects. For example, amoxicillin could be administered to dogs at a dosage of 10 to 20 mg/kg q12h; however, to maintain higher drug concentrations, the same dose could be administered q8h. One method to ensure that the tissue or plasma drug concentration consistently exceeds the MIC is to deliver the antibiotic as a continuous IV infusion. This may be particularly useful in critically ill animals, such as those with urosepsis or those that have an impaired immune response.

1. Recheck urine culture 5 to 7 days into antibiotic therapy. This confirms that the prescribed dose and frequency of the drug were successful in treating the organism isolated. This culture also may reveal an additional isolate that could not be identified in the initial culture. Any bacterial growth observed at this time suggests treatment failure. Reconsider the choice of antibiotic, dose, and administration frequency. 2. Recheck urine culture 3 days before discontinuing antibiotic therapy. This is an

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IN SUMMARY Learn More The International Society for Companion Animal Infectious Diseases (ISCAID) Antimicrobial Working Group Guidelines for Treatment of Urinary Tract Infections are available at iscaid.org/wp-content/ uploads/2013/10/Urinary-guidelines.pdf.

optional step, but it confirms that, when therapy was discontinued, the patient still had a negative culture. Positive bacterial growth at this stage suggests a refractory infection or newly inoculated organism. Investigate patients for any nidus of infection (eg, urolithiasis, anatomic abnormality, local neoplasia). Alter treatment and institute new therapy for the same duration as previously intended. 3. Recheck urine culture 7 days after discontinuing antibiotic therapy. Positive growth should prompt investigation for causes of relapse or reinfection.

Complicated, relapsing, recurrent, and refractory UTI may be challenging to cure. However, understanding drug PK/PD and potential alterations in the animal’s metabolism/excretion of the drug can help increase the likelihood of successful treatment.

Guidelines for appropriate antibiotic dosing for animals with kidney disease have not been established; therefore, a working knowledge of pharmacology and the prescribed drug’s PK/PD profile is needed to help create a successful antibiotic prescription with the smallest risk for adverse effects. When possible, in patients with kidney disease, avoid drugs that have a narrow margin of safety and undergo significant renal elimination (eg, fluoroquinolones in cats, aminoglycosides) and then choose alternative drugs (based on susceptibility results) that undergo hepatic elimination or those with a wide margin of safety. References 1.

Kivistö AK, Vasenius H, Sandholm M. Canine bacteruria. J Small Anim Pract 1977; 18(11):707-712.

2. Wood MW, Breitschwerdt EB, Nordone SK, et al. Uropathogenic E coli promote a paracellular urothelial barrier defect characterized by altered tight junction integrity, epithelial cell sloughing and cytokine release. J Comp Pathol 2012; 147(1):11-19. 3. Weese JS, Blondeau JM, Boothe D, et al. Antimicrobial use guidelines for treatment of urinary tract disease in dogs and cats: Antimicrobial guidelines working group of the international society for companion animal infectious diseases. Vet Med Int 2011; 2011(4):1-9. 4. Wong C, Epstein SE, Westropp JL. Antimicrobial susceptibility patterns in urinary tract infections in dogs (2010-2013). J Vet Inter Med 2015; 29(4):1045-1052. 5. Boothe DM. Principles of antimicrobial therapy. Vet Clin North Am Small Anim Pract 2006; 36(5):1003-1047-vi. 6. Patterson CA, Bishop MA, Pack JD, et al. Effects of processing delay, temperature, and transport tube type on results of quantitative bacterial culture of canine urine. JAVMA 2016; 248(2):183-187. 7. Smee N, Loyd K, Grauer GF. UTIs in small animal patients: Part 2: Diagnosis, treatment, and complications. JAAHA 2013; 49(2):83-94. 8. Ling GV. Therapeutic strategies involving antimicrobial treatment of the canine urinary tract. JAVMA 1984; 185(10):1162-1164.

Author’s Note The lack of data and the limitations in well-designed studies prevent complete evidence-based guidelines from being described for treatment of urinary tract infection (UTI). This article presents an approachable and logical process for treating UTI; however, it too lacks clinical validation. The usefulness of urine drug concentrations has been debated, but several textbooks and peer-reviewed manuscripts suggest that these concentrations can play a role in creating a valid antimicrobial drug prescription. In addition, while the clinical success of drug therapy cannot be predicted on urine drug concentration alone, in the absence of individual patient drug therapeutic monitoring, glomerular filtration rate testing, and urine drug bactericidal assessment data, there are few hard facts on which to base therapy. This article focuses on relevant topics in drug pharmacokinetics/pharmacodynamics, urine susceptibility testing, and educated drug therapy, and numerous holes in our understanding prevent these topics from being without question or debate. However, I hope this article helps increase the understanding of drug pharmacology, where it pertains to UTI, to the best of our understanding. —JD Foster, VMD, DACVIM

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FOCUS ON PHARMACOLOGY 9. Dowling PM. Antimicrobial therapy of urinary tract infections. Can Vet J 1996; 37(7):438-441. 10. Toutain PL, del Castillo JRE, Bousquet Mélou A. The pharmacokineticpharmacodynamic approach to a rational dosage regimen for antibiotics. Res Vet Sci 2002; 73(2):105-114. 11. Toma S, Colombo S, Cornegliani L, et al. Efficacy and tolerability of once-daily cephalexin in canine superficial pyoderma: An open controlled study. J Small Anim Pract 2008; 49(8):384-391. 12. Frimodt-Møller N. Correlation between pharmacokinetic/ pharmacodynamic parameters and efficacy for antibiotics in the treatment of urinary tract infection. Int J Antimicrob Agents 2002; 19(6):546-553. 13. McKinnon PS, Davis SL. Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases. Eur J Clin Microbiol Infect Dis 2004; 23(4):271-288. 14. Gebru E, Choi MJ, Lee SJ, et al. Mutant-prevention concentration and mechanism of resistance in clinical isolates and enrofloxacin/ marbofloxacin-selected mutants of Escherichia coli of canine origin. J Med Microbiol 2011; 60(Pt 10):1512-1522. 15. Schentag JJ. Clinical pharmacology of the fluoroquinolones: Studies in human dynamic/kinetic models. Clin Infect Dis 2000; 31 Suppl 2:S40-S44.

JD Foster

JD Foster, VMD, DACVIM, is a board-certified internist with clinical and research interests in nephrology and urology. He is the director of the Extracorporeal Therapies Service at Friendship Hospital for Animals in Washington, DC. His research interests include drug pharmacokinetics in renal disease, nontraditional uses of extracorporeal blood purification, acute kidney injury, and glomerulonephritis.

Glossary AUC area under the curve

16. Liu H, Mulholland SG. Appropriate antibiotic treatment of genitourinary infections in hospitalized patients. Am J Med 2005; 118(7):14-20.

CLSI Clinical Laboratory Standards Institute

17. Clare S, Hartmann FA, Jooss M, et al. Short- and long-term cure rates of short-duration trimethoprim-sulfamethoxazole treatment in female dogs with uncomplicated bacterial cystitis. J Vet Intern Med 2014; 28(3):818-826.

GFR glomerular filtration rate

18. Westropp JL, Sykes JE, Irom S, et al. Evaluation of the efficacy and safety of high dose short duration enrofloxacin treatment regimen for uncomplicated urinary tract infections in dogs. J Vet Intern Med 2012; 26(3):506-512. 19. Jessen LR, Sørensen TM, Bjornvad CR, et al. Effect of antibiotic treatment in canine and feline urinary tract infections: A systematic review. Vet J 2015; 203(3):270-277.

Cmax peak drug concentration MIC minimum inhibitory concentration PD pharmacodynamics PK pharmacokinetics UTI urinary tract infection

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How to Be Prepared for Most Toxic Exposures in Dogs and Cats Laura Stern, DVM ASPCA Animal Poison Control Center, Urbana, Illinois shutterstock.com/panchopastori

Welcome to Practical Toxicology, brought to you in partnership between Today’s Veterinary Practice and the ASPCA Animal Poison Control Center (APCC) (aspcapro.org/poison). This column provides practical clinical information about diagnosing and treating pets that have been exposed to potentially harmful substances. The APCC: •P rovides 24-hour diagnostic and treatment recommendations by specially trained veterinary toxicologists •P rotects and improves animal lives through toxicology education, consulting services, and case data review •D eveloped and maintains AnTox, an animal toxicology database system that identifies and characterizes toxic effects of substances in animals •W orks closely with human poison control centers to provide animal poisoning information •O ffers extensive veterinary toxicology consulting to organizations in industry, government, and agriculture. If treating a patient that requires emergency care for poisoning, call the APCC at 888-426-4435.

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It can be daunting to try to figure out what you need to have on hand to treat toxicologic cases. When making decisions, it is most helpful to break down the treatment into 2 phases: decontamination and clinical management. In the decontamination phase, treatments are focused on removing the toxin before it can be absorbed further and/or diluting the toxin to reduce local irritation. In the management phase, clinical signs need to be reversed or minimized. A surprising number of the medications needed to treat intoxications may already be present in the hospital’s pharmacy, as many are used for other indications in veterinary medicine. The medications needed for treating toxicoses fall into 2 groups: (1) those to keep on hand for emergencies and (2) those that should be quickly obtainable when warranted. The latter group are either readily available at a human pharmacy or hospital (cholestyramine and N-acetylcysteine), are not needed peracutely (pamidronate), or are extremely expensive and only used for rare toxicoses (digoxin immune Fab).

PRACTICAL TOXICOLOGY

INVENTORY TO KEEP ON HAND Decontamination Liquid Dishwashing Detergent and Shampoo

Bathing a pet with liquid dishwashing detergent, antiseborrheic shampoo, or a follicular flushing shampoo is helpful in removing any greasy or oily substances from the hair coat. Bathing is often recommended when it is necessary to remove topical flea medication from the hair coat, such as for a cat exposed to a permethrin product. All patients should be stabilized before bathing, and care should be taken to prevent chilling, especially with small or young pets. Sterile Eye Irrigation Solution

Ocular exposure to irritating or corrosive substances may require 20 to 30 minutes of ocular flushing with a sterile eye irrigation solution, with breaks as needed to help reduce the stress to the pet. This may require copious amounts of irrigation solution, which may be unreasonable to have on hand. As an alternative, sterile saline or room-temperature water can be used to flush the affected eye(s). Apomorphine

Apomorphine is a centrally acting emetic. Inducing emesis is contraindicated in cases where the patient has ingested a petroleum distillate or caustic substance; in patients that are already vomiting, are showing clinical signs, or have underlying health issues that would make emesis unsafe; and in species that are unable to vomit. Apomorphine can be very helpful in preventing the absorption of a toxin by inducing emesis in asymptomatic dogs that have recently ingested toxins. Emesis in dogs is mediated through dopamine receptors in the chemoreceptor trigger zone, which are stimulated by apomorphine. Apomorphine can cause sedation, which in some cases can be excessive and make emesis unsafe because of the risk of aspiration. Naloxone can safely be given to dogs to reverse this sedation without reversing the emetic effects of the apomorphine.1

It is important to note that apomorphine is not an effective emetic for cats because emesis is mediated by α2-adrenergic receptors in the chemoreceptor trigger zone in this species. α2-Adrenergic agonists, such as xylazine and dexmedetomidine, are better choices for attempting to induce emesis in cats. Activated Charcoal

The large surface area of activated charcoal makes it very useful in adsorbing toxicants that are still in the GI tract or that undergo enterohepatic recirculation. Activated charcoal should be considered in asymptomatic pets with recent exposures to toxicants with the potential to cause serious clinical signs. Activated charcoal is not beneficial in cases in which heavy metals, corrosive agents, hydrocarbons, fluoride, xylitol, ethanol, and/or petroleum distillates are ingested. Activated charcoal is contraindicated with salt or paintball toxicosis, as it adds to the risk of hypernatremia. The risk of aspiration should be considered in animals that are unable to swallow or to protect their airway or in cases of uncontrolled vomiting or regurgitation. The risk of hypernatremia, which can be life-threatening, should also be considered prior to administration, especially with pets that are small, dehydrated, or have ingested osmotically active substances (eg, chocolate, sugar). Serum sodium monitoring and fluid administration should be considered when activated charcoal is given.

Management Acepromazine

Acepromazine is a phenothiazine sedative. It is helpful for treating the clinical signs of stimulation in a wide number of toxicoses, including amphetamine, selective serotonin reuptake inhibitor (SSRI), 5-hydroxytryptophan (5-HTP), selective serotonin and norepinephrine reuptake inhibitor (SSNRI), and phenylpropanolamine (PPA) toxicoses. Acepromazine can cause hypotension, and blood pressure monitoring should be considered, especially if treating a toxicosis that can also cause hypotension.

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Atropine

Methocarbamol

Atropine is an anticholinergic medication that is a competitive antagonist to acetylcholine at muscarinic receptor sites.2 It is used to treat SLUDDE signs (salivation, lacrimation, urination, defecation, dyspnea, emesis) associated with organophosphate and carbamate toxicosis, Solanum plant toxicosis, and clitocybe and inocybe mushroom toxicosis.3 It can be used at lower doses to correct bradycardia caused by other toxins.3 Atropine is contraindicated in patients with reflex bradycardia secondary to hypertension.

Methocarbamol is a centrally acting skeletal muscle relaxant. It is used for tremor control and rigidity in animals with permethrin, metaldehyde, tetanus, tremorgenic mycotoxin, hops (Humulus lupulus), and strychnine intoxications.4 Methocarbamol can provide relief for tremors in some situations when other medications are unlikely to be effective.

Atipamezole

Atipamezole is an α2-adrenergic antagonist that can be used to reverse α2-adrenergic agonists, such as those used in veterinary medicine like amitraz and xylazine. Atipamezole can be used to reverse sedation, bradycardia, and hypotension caused by α2-adrenergic agonists.4 It is also useful to reverse the effects of human medications, such as clonidine and tizanidine (synthetic imidazoline derivatives used to treat hypertension and ADHD), and imidazoline decongestants in eyedrops. Vitamin K1

Vitamin K1 (phytonadione) is used to treat coagulopathy caused by anticoagulant rodenticide toxicosis, and/or warfarin overdoses. These anticoagulants block vitamin K–dependent clotting factor synthesis by inhibiting the K 1-2,3-epoxide reductase enzyme. This halts the recycling of vitamin K1 and causes a deficiency. Supplementation with high doses of vitamin K1 corrects this deficiency. Vitamin K1 is not stored in the liver, so daily or twice daily dosing is indicated. With cases of recent exposure to an anticoagulant, it can be used to prevent clinical signs from developing. In animals with evidence of active bleeding, it will take 6 to 12 hours to start to produce additional clotting factors and appropriate supportive care and blood transfusions should be considered until the prothrombin time (PT) returns to normal.3 Vitamin K1 can also be used with coagulopathy secondary to liver failure (such as with severe xylitol toxicosis).

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Injectable Beta Blockers

Beta blockers block β-1 (and some nonselective beta blockers also block β-2) adrenergic receptors in the myocardium. Beta blockers are indicated for reducing tachycardia. Injectable propranolol and/or esmolol are the most commonly stocked beta blockers for the treatment of toxicoses. They are especially useful for the treatment of tachycardia in albuterol, amphetamine, and methylxanthine toxicoses. Naloxone

Naloxone is an opioid antagonist that competes with and displaces opioids at mu, kappa, and sigma receptors. The reversal of opioids occurs within a few minutes, and significant clinical signs should be rapidly apparent. Naloxone also can be used in dogs to reverse central nervous system (CNS) effects associated with high-dose ibuprofen toxicosis. Injectable Benzodiazepines

Benzodiazepines (eg, diazepam) increase the action of gamma-aminobutyric acid (GABA) by binding to A-type GABA receptors and opening the membrane channels, allowing the entry of chloride ions and hyperpolarizing the cell. The increased GABA activity results in CNS depression and depressed spinal reflexes. Benzodiazepines are useful for their antiepileptic and sedative properties when used to treat toxicoses in veterinary patients. They are indicated for controlling seizures in these cases. However, they should be used with caution to control signs of amphetamine toxicosis other than seizures, as it can worsen the disorientation and clinical signs of stimulation.

PRACTICAL TOXICOLOGY

Dextrose

Digoxin Immune Fab

Dextrose can be used to prevent or treat hypoglycemia secondary to toxicosis caused by xylitol, sulfonylureas (such as glimepiride, glipizide, and glyburide), sago palm (Cycas revoluta), amphetamines, or death cap mushrooms (Amanita phalloides) and hypoglycemia secondary to acute liver injury. Dextrose may also be hepatoprotective in cases of sago palm or xylitol toxicosis.

Digoxin immune Fab (Digibind™) fragments are antidigoxin antibodies that bind directly to digoxin and inactivate it.3 Digoxin immune Fab can be used for the treatment of digoxin, bufotoxin (from bufotoxin-containing toads in the Bufo and Rhinella genuses), and digitalis glycoside–containing plant (such as Nerium oleander) toxicoses. Digoxin immune Fab has been used in small animals and has proven to be efficacious, but it is reserved for lifethreatening cases of toxicosis, as it is quite expensive and less severe toxicities can often be managed medically.6 It can reverse severe bradyarrhythmias and tachyarrhythmias not responding to conventional therapies. Urine output should be monitored when digoxin immune Fab is used. The digoxin-antibody complexes are renally excreted and can dissociate if the animal is not eliminating them, causing recurrence of the clinical signs.7

MEDICATIONS THAT SHOULD BE QUICKLY OBTAINABLE N-Acetylcysteine N-Acetylcysteine is a glutathione precursor that can be used to prevent or treat methemoglobinemia associated with acetaminophen toxicosis in dogs and cats by maintaining or restoring glutathione levels. When the toxic metabolites of acetaminophen conjugate with glutathione, they are converted to nontoxic metabolites. N-Acetylcysteine can also be administered to attempt to reduce hepatotoxicity associated with ingestion of acetaminophen, xylitol, sago palm, or death cap mushrooms.

Cholestyramine Cholestyramine is a resin that binds with bile acids in the intestine. It forms an insoluble complex with bile acids in the intestines, and they are excreted in the feces. Cholestyramine helps remove toxins bound to bile acids, thus helping to break up enterohepatic recirculation. It has been used off label in overdoses of cholecalciferol and potentially some NSAID toxicoses.

Pamidronate Pamidronate is a bisphosphonate used to treat hypercalcemia. It binds to hydroxyapatite in bone and inhibits the osteoclastic bone resorption of calcium. It has been shown to reverse hypercalcemia and hyperphosphatemia in dogs exposed to cholecalciferol.4 Toxicoses from cholecalciferol rodenticides, vitamin D supplements, and vitamin D analogs (eg, calcipotriene) may require treatment with pamidronate. Pamidronate lowers calcium within 24 to 48 hours after administration.5

Fomepizole (4-MP) Fomepizole is an inhibitor of alcohol dehydrogenase used to prevent ethylene glycol intoxication in small animals. Fomepizole binds to alcohol dehydrogenase and prevents it from metabolizing ethylene glycol into metabolites that cause acidosis and acute renal failure. Because fomepizole works by inhibiting the metabolism of ethylene glycol, it is most effective when used early, before ethylene glycol has been metabolized. Fomepizole is superior to ethanol for treatment of ethylene glycol intoxication as it does not worsen the depression or acidosis seen with ethylene glycol and does not cause hyperosmolality.3 Emergency hospitals that routinely see ethylene glycol cases may need fomepizole on hand at all times. For some day practices, it may make more sense to cooperate with other local day practices or emergency hospitals so it is readily available if needed.

Levetiracetam Levetiracetam is a pyrrolidone nootropic antiepileptic. It can be helpful in some patients with seizures refractory to traditional antiepileptics. Because it is typically given to patients with severe seizures that are not likely MARCH/APRIL 2017

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chewables

CAUTION: Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian. INDICATIONS: For use in dogs to prevent canine heartworm disease by eliminating the tissue stage of heartworm larvae (Diroﬁlaria immitis) for a month (30 days) after infection and for the treatment and control of ascarids (Toxocara canis, Toxascaris leonina) and hookworms (Ancylostoma caninum, Uncinaria stenocephala, Ancylostoma braziliense). DOSAGE: HEARTGARD® Plus (ivermectin/pyrantel) should be administered orally at monthly intervals at the recommended minimum dose level of 6 mcg of ivermectin per kilogram (2.72 mcg/lb) and 5 mg of pyrantel (as pamoate salt) per kg (2.27 mg/lb) of body weight. The recommended dosing schedule for prevention of canine heartworm disease and for the treatment and control of ascarids and hookworms is as follows: Dog Weight

Chewables Per Month

Ivermectin Content

Pyrantel Content

Color Coding 0n Foil Backing and Carton

Up to 25 lb 26 to 50 lb 51 to 100 lb

1 1 1

68 mcg 136 mcg 272 mcg

57 mg 114 mg 227 mg

Blue Green Brown

HEARTGARD Plus is recommended for dogs 6 weeks of age and older. For dogs over 100 lb use the appropriate combination of these chewables. ADMINISTRATION: Remove only one chewable at a time from the foil-backed blister card. Return the card with the remaining chewables to its box to protect the product from light. Because most dogs find HEARTGARD Plus palatable, the product can be offered to the dog by hand. Alternatively, it may be added intact to a small amount of dog food. The chewable should be administered in a manner that encourages the dog to chew, rather than to swallow without chewing. Chewables may be broken into pieces and fed to dogs that normally swallow treats whole. Care should be taken that the dog consumes the complete dose, and treated animals should be observed for a few minutes after administration to ensure that part of the dose is not lost or rejected. If it is suspected that any of the dose has been lost, redosing is recommended. HEARTGARD Plus should be given at monthly intervals during the period of the year when mosquitoes (vectors), potentially carrying infective heartworm larvae, are active. The initial dose must be given within a month (30 days) after the dog’s first exposure to mosquitoes. The final dose must be given within a month (30 days) after the dog’s last exposure to mosquitoes. When replacing another heartworm preventive product in a heartworm disease preventive program, the first dose of HEARTGARD Plus must be given within a month (30 days) of the last dose of the former medication. If the interval between doses exceeds a month (30 days), the efficacy of ivermectin can be reduced. Therefore, for optimal performance, the chewable must be given once a month on or about the same day of the month. If treatment is delayed, whether by a few days or many, immediate treatment with HEARTGARD Plus and resumption of the recommended dosing regimen will minimize the opportunity for the development of adult heartworms. Monthly treatment with HEARTGARD Plus also provides effective treatment and control of ascarids (T. canis, T. leonina) and hookworms (A. caninum, U. stenocephala, A. braziliense). Clients should be advised of measures to be taken to prevent reinfection with intestinal parasites. EFFICACY: HEARTGARD Plus Chewables, given orally using the recommended dose and regimen, are effective against the tissue larval stage of D.immitis for a month (30 days) after infection and, as a result, prevent the development of the adult stage. HEARTGARD Plus Chewables are also effective against canine ascarids (T. canis, T. leonina) and hookworms (A. caninum, U. stenocephala, A. braziliense). ACCEPTABILITY: In acceptability and field trials, HEARTGARD Plus was shown to be an acceptable oral dosage form that was consumed at first offering by the majority of dogs. PRECAUTIONS: All dogs should be tested for existing heartworm infection before starting treatment with HEARTGARD Plus which is not effective against adult D. immitis. Infected dogs must be treated to remove adult heartworms and microfilariae before initiating a program with HEARTGARD Plus. While some microfilariae may be killed by the ivermectin in HEARTGARD Plus at the recommended dose level, HEARTGARD Plus is not effective for microfilariae clearance. A mild hypersensitivity-type reaction, presumably due to dead or dying microfilariae and particularly involving a transient diarrhea, has been observed in clinical trials with ivermectin alone after treatment of some dogs that have circulating microfilariae. Keep this and all drugs out of the reach of children. In case of ingestion by humans, clients should be advised to contact a physician immediately. Physicians may contact a Poison Control Center for advice concerning cases of ingestion by humans. Store between 68°F - 77°F (20°C - 25°C). Excursions between 59°F - 86°F (15°C - 30°C) are permitted. Protect product from light.

to be able to safely take medication orally, the injectable preparation should be stocked. Levetiracetam seems to be particularly helpful in the treatment of severe seizures seen with 5-fluorouracil toxicosis, although these can be refractory even to levetiracetam.8

SUMMARY It is not necessary to have thousands of dollars of specialized medications on hand to be able to treat most toxicology emergencies. A small investment in some stock (many of the medications should already be in the hospital) and knowing where and how to obtain other medications quickly will give most veterinarians the confidence and ability to be prepared to deal with most toxicologic emergencies. References 1.

Plumb DC. Apomorphine. In: Plumb's Veterinary Drug Handbook. 8th ed. Ames: Wiley-Blackwell; 2015:77-78.

2. Plumb DC. Atropine. In: Plumb's Veterinary Drug Handbook. 8th ed. Ames: Wiley-Blackwell; 2015:93-96. 3. Wismer T. Antidotes. In: Poppenga RH, Gwaltney-Brant S, eds. Small Animal Toxicology Essentials. Sussex: Wiley-Blackwell; 2011:57-70. 4. Khan SA. Common reversal agents/antidotes in small animal poisoning. In: Clinical Veterinary Advisor: Dogs and Cats. St. Louis: Elsevier Mosby;2010:403-406. 5. Rumbeiha WK, Fitzgerald SD, Kruger JM, et al. Use of pamidronate disodium to reduce cholecalciferol-induced toxicosis in dogs. Am J Vet Res 2000;61(1):9-13. 6. DeClementi C. Prevention and treatment of poisoning. In: Gupta RC, ed. Veterinary Toxicology: Basic and Clinical Principles. Amsterdam: Elsevier; 2012:1361-1379. 7. Jesty SA, Reef VB. Cardiovascular system. In: Orsini JA, Divers TJ, eds. Equine Emergencies: Treatment and Procedures. St. Louis: Saunders; 2008:90. 8. Stern L. 5-Fluorouracil. In: Hovda L, Brtulag A, Poppenga R, Peterson K, eds. Blackwell's Five-Minute Veterinary Consult: Small Animal Toxicology. 2nd ed. Ames: Wiley-Blackwell; 2016:119-125.

ADVERSE REACTIONS: In clinical ﬁeld trials with HEARTGARD Plus, vomiting or diarrhea within 24 hours of dosing was rarely observed (1.1% of administered doses). The following adverse reactions have been reported following the use of HEARTGARD: Depression/lethargy, vomiting, anorexia, diarrhea, mydriasis, ataxia, staggering, convulsions and hypersalivation. SAFETY: HEARTGARD Plus has been shown to be bioequivalent to HEARTGARD, with respect to the bioavailability of ivermectin. The dose regimens of HEARTGARD Plus and HEARTGARD are the same with regard to ivermectin (6 mcg/kg). Studies with ivermectin indicate that certain dogs of the Collie breed are more sensitive to the effects of ivermectin administered at elevated dose levels (more than 16 times the target use level) than dogs of other breeds. At elevated doses, sensitive dogs showed adverse reactions which included mydriasis, depression, ataxia, tremors, drooling, paresis, recumbency, excitability, stupor, coma and death. HEARTGARD demonstrated no signs of toxicity at 10 times the recommended dose (60 mcg/kg) in sensitive Collies. Results of these trials and bioequivalency studies, support the safety of HEARTGARD products in dogs, including Collies, when used as recommended.

Laura Stern

Dr. Laura Stern received her DVM from Michigan State University in 2005. After 4 years in small animal private practice, she decided to challenge herself by coming to work for the ASPCA Animal Poison Control Center in 2009. She has written a book chapter on attention-deficit hyperactivity disorder medications and articles on lamotrigine, hypertonic sodium phosphate enemas, and fipronil toxicosis in rabbits. She lives with her husband, daughter, 5 cats, and tiny dog.

HEARTGARD Plus has shown a wide margin of safety at the recommended dose level in dogs, including pregnant or breeding bitches, stud dogs and puppies aged 6 or more weeks. In clinical trials, many commonly used ﬂea collars, dips, shampoos, anthelmintics, antibiotics, vaccines and steroid preparations have been administered with HEARTGARD Plus in a heartworm disease prevention program. In one trial, where some pups had parvovirus, there was a marginal reduction in efﬁcacy against intestinal nematodes, possibly due to a change in intestinal transit time. HOW SUPPLIED: HEARTGARD Plus is available in three dosage strengths (See DOSAGE section) for dogs of different weights. Each strength comes in convenient cartons of 6 and 12 chewables. For customer service, please contact Merial at 1-888-637-4251.

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PRACTICAL TOXICOLOGY

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Data on file at Merial. Freedom of Information: NADA140-971 (January 15, 1993).

IMPORTANT SAFETY INFORMATION: HEARTGARD® Plus (ivermectin/pyrantel) is well tolerated. All dogs should be tested for heartworm infection before starting a preventive program. Following the use of HEARTGARD Plus, digestive and neurological side effects have rarely been reported. For more information, please visit www.HEARTGARD.com.

PREVENTS HEARTWORM DISEASE

TREATS AND CONTROLS 3 SPECIES OF HOOKWORMS

TREATS AND CONTROLS 2 SPECIES OF ROUNDWORMS

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