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VOL. 16 - (1) - APRIL 2006 ISSN 1018-2357 The European Journal of Companion Animal Practice Canine inflammatory bowel disease 33 The safe use of cytotoxic drugs in companion animal practice 51 Mandibulectomy and maxillectomy as a treatment for bone invasive oral neoplasia in the dog 73 Feline paediatric medicine 83 THE OFFICIAL JOURNAL OF FECAVA Federation of European Companion Animal Veterinary Associations www.fecava.org (EJCAP) Volume 16 (1) April 2006 The Official Journal of the Federation of European Companion Animal Veterinary Associations (FECAVA). Editor Dr. Keith DAVIES 43, Hill Top Road - Newmillerdam GB-WF2 6PZ Wakefield Tel.: (44) 1924 250486 (UK) (33) 4 68 39 50 29 (F) Fax: (44) 1924 259572 Email: [email protected] Production Committee Dr Ellen BJERKÅS, FECAVA President Dr. Keith DAVIES, Editor Dr. Maurice ROZE Dr. Joaquin ARAGONES Dr. Peter STERCHI Dr. Tiina TOOMET Dr. Johan VAN TILBURG Dr. Simon KLEINJAN Editorial board (for new work) DERMATOLOGY Didier-Noël CARLOTTI (F) CARDIOLOGY Anna TIDHOLM (S) INTERNAL MEDICINE Åke HEDHAMMAR (S) ORTHOPAEDICS Aldo VEZZONI (I) SURGERY Simon ORR (GB) IMAGING Ingrid GIELEN (B) Eiliv SVALASTOGA (DK) REPRODUCTION Stefano ROMAGNOLI (I) DENTISTRY Peter FAHRENKRUG (D) OPHTHALMOLOGY Ellen BJERKÅS (N) NEUROLOGY Andre JAGGY (CH) ENDOCRINOLOGY Mike HERRTAGE (GB) ONCOLOGY Jane DOBSON (GB) Material should be sent to: Prof.Ellen BJERKÅS, Norwegian School of Veterinary Science, PO Box 8146-Dep, N- 0033, Oslo. Advertisement bookings Sould be sent to: The Editor (see above) Circulation Members of the Associations belonging to the Federation of European Companion Animal Veterinary Associations receive the European Journal of Companion Animal Practice at no charge (30,000 copies). Purchase of copies For others interested in purchasing copies the price is 52 € per Volume (2 issues). Orders should be sent to: FECAVA Bookkeeping - Valeriusstraat 255-2 NL-1075 GB Amsterdam The Netherlands Thanks The production Committee of EJCAP thanks: Dr. Keith Davies Prof. Peter Holt Dr. Tim Hutchinson Dr. Edmund Shillabeer Dr. Paul Wotton who have spent time correcting the translations. DISCLAIMER “The Federation of European Companion Animal Veterinary Associations and the Production Committee of the European Journal of Companion Animal Practice accept no responsibility for any omissions and/or errors in information printed in this journal.We specifically draw readers attention to the need to follow instructions of manufacturers products. In any specific situation readers are strongly advised not merely to rely on the material contained in the journal. Any views and opinions expressed are those of the writer and not the Federation or the Production Committee.” Editore SCIVAC-AIVPA, Via Trecchi 20 I-26100, CREMONA, Italia. Inscrizione Registro Stampa del Tribunale di Cremona N.257 del 1/2/1991; Spedizione in abbonamento postale. 45% Art. 2 Comma 20/B - Legge 662/96 1er semestre 2006 - Filiale de Piacenza. Direttore Responsabile : Antonio MANFREDI. Roto Smeets GrafiServices, p.o. box 7052, 3502 KB Utrecht, The Netherlands. Tel +31 (30) 282 28 22 The European Journal of Companion Animal Practice CONTENTS The Federation of European Companion Animal Veterinary Associations (FECAVA)..................................................................2 EDITORIAL .......................................................................................5 NEWS .......................................................................................................10 DERMATOLOGY Application of honey in the treatment of skin wounds P.A.M. Overgaauw, J.Kirpensteijn.............................................. 17 ORTHOPEADICS A case of periosteal proliferative polyarthritis in a cat M. Karayannopoulou, Z.S. Polizopoulou, A.F. Koutinas, M.N. Patsikas,G. Kazakos, A. Fytianou...................................... 21 Putting theory into practice - best practice management for osteoarthritis Stuart Carmichael ..................................................................... 27 GASTROINTESTINAL SYSTEM Canine inflammatory bowel disease: retrospective analysis of diagnosis and outcome in 80 cases (1995-2002) M. Craven, J. W. Simpson, A. E. Ridyard, M. L. Chandler .......... 33 URINARY TRACT Transpelvic urethrostomy (TPU) in the cat: a new technique. Prospective survey: 19 cases A. Bernardé, E. Viguier.............................................................. 41 ONCOLOGY The safe use of cytotoxic drugs in companion animal practice Nick Bexfield ............................................................................. 51 The future of Biomarkers and Personalised Medicine in Companion Animal Practice S. Mian, K. Slater, T. Cave ......................................................... 63 Mandibulectomy and maxillectomy as a treatment for bone invasive oral neoplasia in the dog – a retrospective analysis of 31 patients Martin Kessler ........................................................................... 73 INTERNAL MEDICINE Feline paediatric medicine Kit Sturgess ................................................................................ 83 PARASITOLOGY Autochthonous infections with Angiostrongylus vasorum in dogs in Switzerland and Germany S. Staebler, H. Ochs, F. Steffen, F. Naegeli, N. Borel, N. Sieber-Ruckstuhl, P. Deplazes................................................ 95 PRACTICE MANAGEMENT Patterns in Practice ownership: a UK perspective F. J. Marshall ........................................................................... 101 Book Reviews...............................................................................106 Calendar of main European national meetings and other continuing education opportunities ............................................110 Secretariat or address to contact for information .......................112 THE FEDERATION OF EUROPEAN COMPANION ANIMAL VETERINARY ASSOCIATIONS (FECAVA) FECAVA Headquarter's address: C/O Federation of Veterinarians of Europe rue Defacqz, 1 B-1000 Brussels Tel: +32 2 538 29 63 – Fax: +32 2 537 28 28 FECAVA Website: www.fecava.org Participating Associations: – AFVAC (CNVSPA) (Association Française des Vétérinaires pour Animaux de Compagnie) Director: Dr. Maurice ROZE – AIVPA (Associazione Italiana Veterinari Piccoli Animali) Director: Dr. Guiseppe TRANCHESE – APMVEAC (Associação Portuguese de Médicos Veterinários Especialistas em Animais de Companhia) Director: Dr. Joaquim Vieira LOPEZ – AVEPA (Associatión Veterinaria Española de Especialistas en Pequeños Animales) Director: Dr. Juan Francisco RODRIGUEZ – BASAV (Bulgarian Small Animal Veterinarians) Director: Dr. Boyko GEORGIEV – BHSAVA (Bosnia and Herzegovina Small Animal Veterinary Association) Director: Dr. Josip KRASNI – BSAVA (British Small Animal Veterinary Association) Director: Dr. Simon ORR – CSAVA (Czech Small Animal Veterinary Association) Director: Dr. Jiri BERANEK – CSAVS (Croatian Small Animal Veterinary Section) Director: Dr. Davorin LUKMAN – DSAVA (Danish Small Animal Veterinary Association) Director: Dr. Joergen MIKKELSEN – ESAVA (Estonian Small Animal Veterinary Association) Director: Dr. Tiina TOOMET – FAVP (Finnish Association of Veterinary Practitioners) Director: Dr. Kai SITTNIKOW – GSAVA (German Small Animal Veterinary Association) Director: Dr. Peter FAHRENKRUG – HSAVA (Hungarian Small Animal Veterinary Association) Director: Dr. Julianna THUROCZY – HVMS (Hellenic Veterinary Medical Society) Director: Dr. Katerina LOUKAKI – LAK (Letzebuerger Associatioun vun de Klengdeiere - Pracktiker) Director: Dr. Liz JUNIO – LSAPS (Latvian Small Animal Practitioners Section of The Latvian Association of Veterinarians) Director: Dr. Lita KONOPORE – LSAVA (Lithuanian Small Animal Veterinary Association) Director: Dr. Saulius LAURUSEVICIUS – MSAVA (Macedonion (Fyrom) Small Animal Veterinary Association) Director: Dr. S. COKREVSKI – MVA (Malta Veterinary Association) Director: Dr. L. VELLA, Dr. A. GRUPETTA – NACAM (Netherlands Association for Companion animal Medicine) Director: Dr. Leen DEN OTTER – NSAVA (Norwegian Small Animal Veterinary Association) Director: Dr. Kjetil DAHL – PSAVA (Polish Small Animal Veterinary Association) Director: Dr. Jerzy GAWOR – RSAVA (Russian Small Animal Veterinary Association) Director: Dr. S. SEREDA – SAVAB (Small Animal Veterinary Association of Belgium) Director: Dr. J. van TILBURG – SCIVAC (Società Culturale Italiana Veterinari per Animali da Compagnia) Director: Dr. Dea BONELLO – SkSAVA (Slovakia Small Animal Veterinary Association) Director: Dr. Tibor BRAUNER – SMASAP (Serbia and Montenegro Association of Small Animal Practitioners) Director: Dr. Denis NOVAK – SSAVA (Swedish Small Animal Veterinary Association) Director: Dr. Anne CARLSWÄRD – SVK/ASMPA (Schweizerische Vereinigung für Kleintiermedizin/Association Suisse pour la Médecine des Petits Animaux) Director: Dr. Peter STERCHI – SZVMZ (Slovensko Zdruzenje Veterinariev Za Male Zivali) Director: Dr. Bojan ZORKO – TSAVA (Turkish Small Animal Veterinary Association) Director: Prof. Mustafa AKTAS – USAVA (Ukrainian Small Animal Veterinary Association) Director: Dr. Vladlen Mykhaylovich USHAKOV – VICAS (Veterinary Ireland Companion Animal Society) Director: Dr. Peter A. MURPHY – VÖK (Vereinigung Österreichischer Kleintier mediziner) Director: Dr. Silvia LEUGNER Associate Associations: – EAVS (European Association for Veterinary Specialisation) Contact: Dr. Hans KOCH – ECVD (European College of Veterinary Dermatology) Contact: Dr. Dominique HERIPRET – ECVS (European College of Veterinary Surgeons) Contact: Mrs Monika GUTSCHER – ESVC (European Society of Veterinary Cardiology) Contact: Dr. Chris AMBERGER – ESFM (European Society for Feline Medicine) Contact: Claire BESSANT – ESVCE (European Society of Veterinary Clinical Ethology) Contact: Dr. Sarah HEATH – ESVD (European Society of Veterinary Dermatology) Contact: Dr. Chiara NOLI – ESVIM (The European Society of Veterinary Internal Medicine) Contact: Dr. F.P. GASCHEN – ESVN (European Society of Veterinary Neurology) Contact: Dr. Gualtiero GANDINI – ESVOT (European Society of Veterinary Orthopaedics & Traumatology) Contact: Dr. Aldo VEZZONI – EVDS (European Veterinary Dental Society) President: Dr. Margarita GRACIS – EVSSAR (European Veterinary Society for Small Animal Reproduction) Contact: Dr. Catherina LINDE-FORSBERG FECAVA Officers: Dr. Ellen BJERKÅS (NSAVA) President Dr. Andrew BYRNE (VICAS) Vice-President Dr. Simon KLEINJAN (NACAM) Senior Vice-President Dr. Simon ORR (BSAVA) Secretary Dr Johan van TILBURG (SAVAB) Treasurer ® IAM S C L IN ICAL N UT R IT IO N SY MPO S I U M ® “Life is movement; movement is life” (Aristotle 384-322BC) International experts discuss advances in veterinary and human medicine to improve mobility When we think of “quality of between human and canine mobility, and in particular how life”, whether it is for humans or canine mobility and state-of-the-art joint replacement can pets, freedom of movement is a benefit human health. It seems that both human doctors key component and is associated and veterinarians are increasingly treating behaviour and with health and positive interac- lifestyle-influenced diseases which are in fact preventable. tion with the environment. Yet with the prevalence of mobility- The press conference, featuring a panel of leading veterinary related morbidity on the rise, experts, also confirmed that trends in human sedentary life- nutrition and physical activity are styles are being replicated in pets and it is known that an playing an increasingly important role in preventative care. overweight pet owner is more likely to have an overweight Veterinarians play a crucial role in providing advice, treatment pet. It was concluded that veterinary expertise combined with and guidance on many aspects relating to pets’ mobility. the education of the pet owner was ultimately the route to improving the mobility and long-term well-being of pets, and To discuss these important areas of veterinary medicine, The could also help improve the owner’s lifestyle and well-being. Iams Company brought together renowned expert speakers The Iams Company is celebrating its 60th anniversary this and 240 veterinary guests from 20 European countries and year and has been setting the standards in innovative dog South Africa for a Clinical Nutrition Symposium on “Mobility – a multi-disciplined approach”, held on 11 February 2006 in Montreux, Switzerland. The speakers approached the topic of mobility from many different angles: from diagnostic imaging, to arthroscopy and surgical joint repair, as well as the impact that nutrition, physiotherapy and rehabilitation can have on the orthopaedic patient. The symposium highlighted an interesting parallel Speakers from left to right: Professor Dr. H. van Bree, Veterinary Faculty, Ghent University, Belgium. John Houlton, Cambridge University Veterinary School, United Kingdom. Dr. Jean-François Bardet, Veterinary Clinic Neuilly Sur Seine, France. Dr. Daniel Carey, Research and Development Division, The Iams Company, Ohio, USA. Professor Dr. Ulrike Matis, Ludwig-Maximilians-University Munich, Germany. Professor Dr. Volkmar Jansson, University Clinic Grosshadern, München, Germany. Barbara Bockstahler, University of Veterinary Medicine, Vienna, Austria. Erik Hemmingsson, Karolinska University Hospital Stockholm, Sweden. David Morgan, The Iams Company, Geneva, Switzerland. and cat nutrition for decades. For more information about the Iams Clinical Nutrition Symposium, a copy of the proFrom left to right: Erik Hemmingsson, Karolinska University Hospital, Stockholm, Sweden, Dr. Jean-François Bardet, Veterinary Clinic Neuilly Sur Seine, France, Dr. Daniel Carey, Research and Development Division, The Iams Company, Ohio, USA, Barbara Bockstahler, University of Veterinary Medicine, Vienna, Austria, David Morgan, The Iams Company, Geneva, Switzerland ceedings or the press conference report, please contact your Iams Veterinary Sales Representative or download from www.eukanuba-scienceonline.com. EDITORIAL THE CHANGING STYLE OF VETERINARY PRACTICE What will tomorrow’s companion animal veterinary practice be like? What will be the main influences on this ? The traditional style of practice has evolved over the years. In many countries practices used to be mixed, treating all species, large and small, and they were at one time predominantly single-vet practices. Over the years, practice size has grown to multi-vet and multi-branch in many countries and specialization has occurred. Initially demarcation was by main species groups e.g. Companion animal, Equine and Farm Animal etc. As veterinary science has evolved, specialization by clinical discipline has grown. Initially this was largely confined to veterinary teaching institutions but now private specialist referral practices are becoming increasingly common. All these changes mirror the scientific developments within the field of veterinary medicine and surgery, and the trend towards continuous post-graduate education. The commercial aspect of practice is an integral part of delivering quality veterinary services. It is perhaps inevitable that as the scientific evolution of practice has developed that practice management is open to influence by business models for service delivery from other sectors. We are now seeing an evolution in the style of delivery of veterinary services that mirror the demands of the consumer more than just mirroring the trends in education and scientific development. These evolutionary shifts challenge the traditional models of ownership, organization, style and delivery. These new models include corporate groups of chain practices in which the ownership is centralized within a limited company or shared between a central investment group and the owner-operator of the individual practice unit. Individual presentation of premises is replaced in some by a branded corporate identity. The traditional range of services is challenged with the advent of selected service clinics e.g. vaccination clinics and neutering clinics. The introduction of after-hours emergency centres is also spreading in some European countries. Precedents are established and dissemination of ideas is probably inevitable. This is change – some of which will be judged to be progressive and welcome while some will be regarded as challenging traditional values and therefore unwelcome. FECAVA wishes to highlight some these new models to inform and stimulate debate. Therefore the “practice profile” in this issue will illustrate a selection of examples of some of the new practice service models. There is no implicit endorsement or criticism of any of the systems. The intention is simply to illustrate the type of change that is occurring within companion animal practice in Europe. Andrew Byrne, Vice President FECAVA 5 Avian influenza - An update At the time of going to press, avian influenza cases had been diagnosed in wild birds, mainly swans, in several European countries, and the first confirmation of a H5N1 virus in a turkey farm in France had hit the headlines. By the time you read this, the Asian H5N1 virus has probably spread to even more regions in Europe. Poultry farmers and veterinarians are on a permanent look-out. But companion animal veterinarians too, are confronted daily with questions from their clients. Here’s some background information to fill in some (possible) gaps. What is avian influenza and what are the clinical signs? Avian influenza (AI) is a highly infectious disease affecting many avian species, including commercial, wild and pet birds. It is caused by a Type A influenza virus. Clinical disease in terrestrial (non aquatic) birds is severe. Typically, the disease occurs suddenly with affected birds showing oedema of the head, cyanosis of the comb and wattles, dullness, lack of appetite, respiratory distress, diarrhoea and drop in egg production. In severe cases, birds may die without any signs of disease. However, there is considerable variation in the clinical picture and severity of the disease, depending on the strain of virus and the type of bird infected. For example, waterfowl are less likely to be clinically affected and therefore more likely to spread the disease. Post-mortem findings vary considerably but congestion and haemorrhages affecting any organs usually predominate. Necrotic foci may be found in the liver, lungs, spleen and kidneys. There may also be exudates in the air sacs and peritoneum and occasionally a fibrinous pericarditis. How does the disease spread to humans? And between humans? For AI, close contact with birds that have been infected by (or recently died from) the H5N1 virus is required. In Vietnam and Thailand, several intra-familial clusters of infection have been observed. Epidemiological investigation showed that each cluster had a common source of exposure: either their own backyard poultry or dead birds at home. However, the number of human cases in South-East Asia is extremely low: less than 180 cases (of which 90 fatalities) occurred in a region with a population of over two billion — over a two-and-a-half year period. Horizontal transmission is also low: only a couple of infections have occurred in persons (family or nursing staff) caring for a clinically sick patient. I work with birds / have birds at home. How can I protect myself? Again, AI is primarily a disease of birds — not humans. And AI is not the only infection that can be transmitted from birds to people: salmonellosis, chlamydiosis, psittacosis and campylobacteriosis are well-known zoonoses. Good hygiene precautions, which should always be used when working with birds, will also control the risk of exposure to AI. These include: regular hand-washing, avoiding hand-to-mouth contact, thorough cleaning and covering of all cuts and grazes, and eating away from the area where birds are. Furthermore, hand-feeding semi-wild birds such as ducks and swans should be avoided in case of an AI outbreak. So far, no infected pigeons have been detected in Europe. Can I protect myself by having a ‘flu vaccination? Or by taking antivirals? Seasonal influenza vaccines for people have an antigenic composition that is changed annually to match the antigenic drift of the current human epidemic strains: H1N1, H3N2 and influenza-B virus. The likelihood that the N1 antigen of the vaccine might confer cross-protection against H5N1 is remote. Nevertheless, in case of an H5N1 pandemic, it may be recommended for exposed health care professionals to be vaccinated against the seasonal ‘flu in order to avoid a concurrent infection with different viral strains. Antiviral drugs such as oseltamavir (Tamiflu®) might have adverse effects and should not be taken lightly, and certainly not as a prophyaxis if there is no immediate risk. However, they may be used as treatment within 36 hours of the onset of clinical symptoms, and can be taken if so advised by your Health Authorities. Finally, since Pneumococcus is a common pathogen in severe pulmonary infections, the use of a pneumococcal vaccine is considered as a reasonable protection against possible complications. I heard that cats may catch avian influenza, is that true? Experimental studies have shown that felines are highly sensitive to the Asian strain of H5N1 infection. But in these studies, a high titre of inoculum was used. And although there is also some experimental evidence that the virus could spread from cat to cat, there is considerable uncertainty about whether this would take place in a natural setting. Unpublished data indicate that tigers in Thailand became infected after being fed cadavers of infected birds. But as cats are hunters rather than scavengers, the risk that domestic cats would be infected by eating dead (but still infectious) birds during an outbreak, is considered very low. What about a pandemic? AI is primarily a disease of birds. Transmission to humans in close contact with poultry or other birds occurs rarely and only with some strains of AI. There is potential for mutation of AI viruses to new forms of virus that could cause severe disease in humans and spread easily from person to person. Such a mutation may occur tomorrow. Or in ten years. Or never. Nobody is able to predict this. Update prepared by Karin de Lange DVM - [email protected] - with thanks to Vincent Dedet, DVM, Auzalide Santé Animale. Editor’s note Further information can be obtained by navigating the following Websites: In English: DEFRA http://www.defra.gov.uk and for human concerns http://www.hpa.org.uk In Spanish: http://www.msc.es/Diseno/enfermedadesLesiones/enfermedades_transmisibles.htm In French: www.sante.gouv.fr/htm/dossiers/grippe_aviaire/sommaire.htm FVE : http://www.fve.org WHO: http://www.who.int/en WSAVA: http://www.wsava. OIE: www.oie.int 8 FECAVA NEWS FECAVA FIRST AGAIN ! Ellen Bjerkås takes over as President FECAVA is the first of the three main European Veterinary Federations to elect a woman as its President. At the FECAVA Council meeting in Krakow, Ellen Bjerkås was unanimously elected as the Federation’s 6th President. Ellen became a member of the FECAVA Council nine years ago representing Norway. More recently she was FECAVA Treasurer for 2 years carefully managing budgets and financial policy. After this she served two years as Vice-President of the Federation. In addition Ellen has been very active in EJCAP affairs, being a member of the management committee for the last 7 years. She has always been a guardian of the maintenance of high scientific standards in published work, but also has been particularly keen to see a good representation in EJCAP of all Member Associations. In 2000 we started to seek new, non reprint ,work for the Journal and Ellen became Chairman of the Editorial Board. A lot of new work has been submitted, but Ellen has always endeavoured to ensure that papers are carefully peer reviewed. Inevitably this has meant that many papers have been rejected. great demand as an advisor to the Norwegian salmon industry. Whilst she enjoys this very much she tells me that a downside is the necessity of sea trips, often in very inclement weather! In the Norwegian School of Veterinary Science she is highly regarded as a teacher and this means she is a regular speaker in many European countries. I was fortunate to have a good chance to talk to Ellen prior to her assuming office in Krakow. I was a little surprised to find she still has time for non-veterinary hobbies in addition to FECAVA work, teaching and research commitments. Her passions include classical music and a house on the Costa Blanca. The latter is convenient for contacting our Spanish Ellen is highly regarded as a teacher It is difficult to see how Ellen manages to find time to undertake all this work for FECAVA. She is Professor in the Small Animal Section at the Norwegian School of Veterinary Science. She has also an international reputation in fish eye disease and is in Working in the field – Salmon eye examination 10 EJCAP - Vol. 16 - Issue 1 - April 2006 An accomplished family – L>R Inger, Ellen and Astrid Director who has a practice in Alicante – but not quite so simple for others to make contact as her telephone only works on the roof sun terrace! annual FECAVA international congresses, FECAVA continuing education courses and the EJCAP.’ She went on to detail how financial support is provided to national associations with restricted budgets to help them arrange high-quality CE courses. ‘An essential source of good scientific information is the our journal (EJCAP), which has developed significantly during the last few years. The journal is probably the most important “gift” from FECAVA to the federation’s members, and new ideas and improvements are constantly discussed and implemented’ said Ellen. Ellen has two accomplished daughters, the elder, Astrid, is the Editor of the Norwegian Veterinary Journal. Her new ideas and journalistic skills have made a big impact on that Journal. Family background possibly also plays a part as her father is also a Professor in the Norwegian School of Veterinary Science. Her other daughter Inger, has a non-veterinary career as a salesperson for the Dior Company and is also trained as an actress and singer. She told me that she feels that FECAVA should also continue to be actively involved in establishing formal recognition for different groups of practitioners based on quality-controlled continuing education and encourage companion animal practitioners to be constantly concerned about the standard of the clinical work delivered. I asked Ellen how she felt she could help further develop FECAVA. She told me that with the rapid increase in companion animal practice in Europe seen over the last 10-15 years, there are certainly challenges ahead. She said ‘I see the role of FECAVA as being both a political body as well as an organisation involved in continuing education. The latter is achieved through the She feels that science and politics are closely linked, as has been seen at the annual FECAVA symposia concerning animal welfare and hereditary disease control programmes. She went on to say ‘I see the role of FECAVA in these matters not so much as a body repeating the good work that is already being done by different groups, but more as a co-ordinator of efforts and an organisation arranging for people sharing the same interests and concerns to meet and discuss’. Ellen’s ophthalmological skills are appreciated even outside Europe! ‘The role of both companion animal veterinarians is changing. We will have to be more concerned about the human-animal bond and the role of pet animals in a modern society, and we also have a role in educating the public. For this, I think the FECAVA statements are very important. They show our concern in important political matters, and I would like to see more policy statements being discussed and agreed upon.’ The interview was over, as Ellen had to give a lecture at the PSAVA Congress! Keith Davies Editor of EJCAP 11 FECAVA NEWS FECAVA NEWS • Journal News • Election of New FECAVA Board The November 2005 FECAVA Council meeting took place in Krakow, Poland. During the meeting, a new Board was elected: President: Ellen Bjerkås (Norway) Vice President Andrew Byrne (Ireland) Senior Vice President Simon Kleinjan (The Netherlands) Secretary Simon Orr (United Kingdom) Treasurer Johan Van Tilburg (Belgium) Outgoing President, Simon Kleinjan, said it had been a privilege to be at the helm of FECAVA over the last two years and thanked the Board and all Directors for their support and fellowship. In taking over, Ellen Bjerkås complemented Simon on his hard work and enthusiasm and then set out her vision for the next two years. A profile of Ellen is given elsewhere in this issue – we are looking forward to another successful two years! EJCAP Readers’ survey From Ellen Bjerkås (E-mail:[email protected]) The results of the EJCAP readers’ survey that was available on the FECAVA web page (www.fecava.org) have now been edited. As promised, there was a prize draw among those who responded, and the winners of free registration to the FECAVA/WSAVA/CSAVA congress in Prague and of textbooks have been notified. Unfortunately we did not have as many responders as we wished for. However, we extend a great thank you to all who took the time to answer our questions, as a readers’ survey is essential to learn the strengths and weaknesses of the journal. The statistical value of the responses to the different questions is restricted, with a low response from readers. Still, among those who responded, a majority expressed that they read most of the journal and found it to contain useful information with the scientific value being reliable and high. About half on those who responded sometimes discussed the content of the papers with colleagues; however, there were also people who rarely read the scientific papers. Almost half were interested in practice management; this probably reflects that the majority were private practitioners and owners of clinics. It might also be worth noting that almost 1/5 were not particularly interested in ethical issues. Still, this topic is so important that it needs to be focused upon on a regular basis. It would not be wise to base the future of the journal on a restricted number of opinions, but the survey has given the Editor and production subcommittee some guidelines in the development of a better journal for all our readers. As we do value the input from the readers, please e-mail your comments if you have any, or suggestions for improvements. In addition, we plan to repeat the reader survey in some years, hopefully with a somewhat better compliance. Again, thank you to all who responded, your opinion is very valuable in our work with the journal. The new Board L>R: Simon Orr, Ellen Bjerkås, Simon Kleinjan, Andrew Byrne and Johan Van Tilburg • Council meeting in Krakow Jerzy Gawor and our Polish hosts organised a well-attended scientific congress as well as an excellent entertainment programme. The gala dinner featured a display of local traditional dancing. I have to admit this was not what I was expecting from a “pole-dancing” evening – nevertheless I am looking forward to a future meeting in Lapland (silly English joke!). Discussion in Krakow Our new president felt that it was important to maintain high scientific standards in the articles, yet to acknowledge that the majority of members were practitioners rather than specialists. The Board of the Italian association (SCIVAC) had made some constructive suggestions regarding changes to the editorial board of the journal, and these were in line with the way things had been evolving under the supervision of Ellen Bjerkås . Pole Dancing Oncology theme This issue has three Oncology papers, each of interest and importance for different reasons. FECAVA likes to keep its members informed about new and exciting trends in the scientific field. The paper ‘The future of Biomarkers and Personalised Medicine in Companion Animal Practice’ is a good example.Whilst on the face of it the paper may 12 EJCAP - Vol. 16 - Issue 1 - April 2006 appear very technical and ‘State of the Art’ this technology is already becoming available to practising vets, and it is something we will hear a lot more of in the future. The Commissioned paper on the safe use of cytotoxic drugs in companion animal practice contains important essential information for practices using this type of therapy. • An acknowledged Companion Animal Veterinary Practitioner As highlighted in the last issue of FECAVA News, a paper on Acknowledged Veterinarians was to be presented at the November 2005 round of UEVP/FVE meetings. This paper was adopted by the FVE. Acknowledged Veterinarians were defined as practitioners who worked mainly (greater than 50% of their time) with particular species and who had obtained additional experience and qualifications. Such a title was intended to be readily attainable by veterinarians in practice and hence was seen as at a much lower level than the specialisation as defined by the European Board of Veterinary Specialisation. Evaluation might involve a specified period working with an acknowledged/ competent veterinarian, the attendance of targeted CPD courses and perhaps an examination supervised by an acknowledged/ competent veterinary body. Prof Stefano Romagnoli of the European Society for Feline Medicine addressed the delegates at the FECAVA Council on this issue. He discussed the provisions in more detail and suggested that ESFM might be well placed to be the competent European body for the acknowledged feline practitioner. The discussion that followed indicated that some directors present favoured a “companion animal” category rather than separate canine and feline one, though this did not seem possible in terms of the accepted UEVP/FVE proposition. (See also report of debate on specialisation at AFVAC Congress Toulouse Overleaf). The ‘Lincoln Baby Lab’ L>R : Alan Woodford (IT expert, Lincoln), Kerstin Meints (Lincoln University), Soraya Verbeke (Blue Dog Artist) and Tny De Keuster (Blue Dog Trust Chairman) Ray Butcher gave a presentation on the project in Krakow and this was well received by an audience of vets, breeders and teachers. It also attracted significant media interest, and we hope to build on this for Prague. • Vet Nursing The Spring 2005 edition of FECAVA News mentioned the proposed partnership of FECAVA with VETNNET in the Dasvent project. This is aimed at the development of a voluntary accreditation system for veterinary nurse training courses in Europe, and the agreement was finally signed in the autumn of 2005. The main aims of the project include: – The formation of an Accreditation Board (consisting mainly of employers). – The formation of a Visitation Committee (made up of VETNNET, veterinary organisations, vet nurse organisations and qualifying bodies). – Adaptation of the USA Accreditation systems to European Standards (see also WSAVA Activities p. 15). – Development of a syllabus of agreed “competences” for European veterinary nurses. – Testing the accreditation system for acceptability. • Evaluation of Veterinary Schools Dr Olivier Glardon (Switzerland) gave an update to the FVE Assembly on the evaluation of European veterinary schools. Of the 102 schools that were members of the European Association of Establishments for Veterinary Education (EAEVE), 71 had been evaluated at least once and 38 of these had “passed” and were on the so-called “positive” list. One has to wonder about the 33 that have been inspected and not passed, or indeed about the 31 that have never been inspected at all! For more information see www.eaeve.org. Dasvent project coordinator Renze Holwerda (Principal of Groenhorst College) and the then FECAVA Secretary Andrew Byrne signing the agreement. • Blue Dog The Blue Dog project continues to gain momentum, and the BLUE DOG TRUST was finally established as a distinct legal entity in November 2005. Tiny De Keuster of Belgium was elected as Chairman. At the time of writing, the interactive CD is being scientifically tested at the Lincoln University BabyLab. This research project has been funded largely from support given by FECAVA and NACAM (the Small Animal Association of the Netherlands), with additional funds being donated by the BSAVA and the Norwegian Association for pet Behaviourists. The research should be completed by the spring of 2006 and will be presented at the FECAVA/WSAVA congress in Prague in October 2006. 13 FECAVA NEWS countries. They have been working with colleagues from the successful NAVC in Florida to bring in additional expertise and variety and yet maintain a distinct Spanish feel. Watch this space! • Next FECAVA Congress The next FECAVA Congress will be held together with the WSAVA and the Czech Small Animal Veterinary Association in the beautiful and historic city of Prague, October 11 – 14, 2006. For further information check the website: www.wsava2006.cz • Toulouse hosts AFVAC Annual Congress Delegates at the Dasvent meeting From Keith Davies, Editor Ejcap It was a privilege to represent FECAVA at the Annual Congress of AFVAC, the French Small Animal Veterinary Association held in Toulouse. AFVAC (CNVSPA) probably has the strongest link with FECAVA of all its Member Associations. The first FECAVA President was Didier-Noël Carlotti of CNVSPA ,who was in fact instrumental in founding FECAVA. At the Congress Dr. Carlotti was re-elected as President of AFVAC. Maurice Roze, AFVAC’s current representative in FECAVA, was also elected as President of the newly formed Francophone Federation, both these appointments cementing the strong links of AFVAC with FECAVA. The AFVAC Annual Congress has made the bold decision not to locate in Paris each year, but rather to move around the regions of France. Whilst this may slightly reduce the numbers who would attend in the metropolis, it does give veterinarians in other parts of the country a chance to take part without having too much travel. The large attendance of 2825 delegates in Toulouse and the extensive commercial exhibition, attests to the fact that changing the venue does not result in a less successful congress. Didier-Noël Carlotti has also made a big effort to develop Continuing Education activity in regions throughout the whole of France. Another feature of AFVAC’s structure is the key role of specialist divisions within the Association. As I mentioned the Francophone Federation was founded at the Conference. Represenatives from Algeria, Belgium, France, Luxemburg, Morocco, Switzerland and Tunisia, attended the meeting. At first I was a little unclear regarding the reasons for founding such a Federation. It seemed to me that whilst it obviously must be a little irksome to non-English speaking With regard to nursing, AVEPA continue to build on their successful nurse programme in Spain. As well as a nurse session at their annual congress and a number of regional meetings held throughout the year, they have just launched a new Journal aimed at nurses. • Medicines The changes in medicines legislation within Europe continue to be a concern of FECAVA Directors. The last issue of FECAVA News highlighted the proposed changes in the UK. These became law on 31st October 2005, and practitioners are still facing up to the implications these will have on their business and the way they work on a day-to-day basis. Further information is available on www.bsava.com, www.vmd.gov.uk or www.dti.gov.uk • Veterinary Homeopathy – views of the establishment strengthen against its use The debate as to the relative merits of Homeopathy has been raging for some time - antagonists claiming it has no place in evidence-based veterinary medicine, while supporters point to a growing request from the public for such a service. Perhaps the recent declared positions of major European veterinary groups reflects the tightening of the medicines legislation, but whatever the reason the matter has featured in the pages of New Scientist (10th December 2005). This article highlights that in April 2005, “the European Board of Veterinary Specialisation issued a statement warning that its members could lose their status if they offer non-evidence based treatments”. Further to this, in November 2005, the FVE issued a policy statement urging its 200,000 members “to work only on the basis of scientifically proven and evidence-based methods and to stay away from non-evidence-based methods”. Finally, the New Scientist article quotes Jan Vaarten, Executive Director of FVE, as saying “When vets go into homeopathy, it creates a false impression that it is also evidence-based”. I am sure the arguments will continue! From L>R: Didier-Noël Carlotti (President of AFVAC), Francisco Florit (AVEPA) and Javier Villamor (AVEPA). • AVEPA - Enhancement of their future national Congresses AVEPA have announced their plans to enlarge their annual congress in Barcelona to make it more attractive to their own members as well as to attract delegates from other European 14 EJCAP - Vol. 16 - Issue 1 - April 2006 countries, to see the increasing acceptance of English as the main language for international Veterinary communication, this progression was inevitable. Maurice Roze told me there was no conflict of interest here.. French he said, is widely spoken throughout the world, particularly in Europe and Africa. Many Veterinarians in these countries do not read English, and the French language provides an important avenue for the communication of knowledge. The common language binds these countries together both historically and culturally. A Spanish and Portuguese speaking Federation was successfully formed two years ago. The goal of federations such as these should be to offer a complementary tool to already existing international veterinary associations for continuous education and progress in animal health and welfare. I attended a Seminar on the subject of Specialisation in France. It was clear that the same worries and concerns were common to those experienced in other countries. There was a fear by current diplomates and highly specialised and competent veterinary surgeons that the levels of specialisation not requiring full time training and attainable by vets working in practice could constitute a threat. On the other hand there was a strong feeling that practising vets who were unable to take time off to attend full time training should be allowed to achieve some specialist status. The debate was heated and lively and was skilfully chaired by Maurice Roze allowing all the different opinions to be aired. Symposia and subjects which could be regarded as contentious are an important and newly developing feature of AFVAC congresses. The Gala evening at a French congress is almost legendary and an event not to be missed. This year I was a little disappointed to notice that “food” was not part of the evening, an unusual The Halle aux Grains omission in France! I was also apprehensive about the thought of classical music with a humourous twist. Le Quatuor, however held the audience spellbound. Their undoubted ability to perform classical music to a high standard enabled them to introduce humour in an acceptable way. The concert was held in the Halle aux Grains, a historic and attractive venue, kindly provided for the use of AFVAC by the Mayor of Toulouse. In the past I have been to many AFVAC (CNVSPA) national congresses and have always had a very enjoyable weekend. This year was no exception. FECAVA members who do not travel to European Congressess outside there own country are missing exciting scientific and social opportunities. WSAVA ACTIVITIES From Dr Walt Ingwersen WSAVA Editor • WSAVA Adopts Policy on Dangerous Dogs responsibilities in educating the public to enable them to select a suitable dog. They should help advise on the provision of an appropriate environment, and to discourage breeding and distribution of animals with undesirable behaviour traits. Legislative recommendations Effective legislation is required to address the problems posed by individual dangerous dogs. Special regulations regarding the registration/identification of the offending animal with local authorities is needed. Regulations may include the following: 1. Whilst at home, the dog should be kept indoors or in a secure dog-proof enclosure. 2. The owner should be required to display warning signs at the premises, including a sign that children can understand. 3. When the dog is taken off the owner’s premises, it must be muzzled, leashed, and under the effective control of the owner at all times. 4. If a declared dangerous dog becomes a stray, it must be humanely destroyed. 5. If a dog is transported, then it should be within a child-proof enclosure. 6. A declared dangerous dog must have permanent (microchip) identification and wear a collar that is easily recognizable an 1. The WSAVA supports the development of dangerous dog legislation, provided it refers to an individual dog’s measurable actions. 2. The WSAVA does not support the targeting of specific breeds under dangerous dog legislation. Background There are community concerns about the keeping of certain breeds of dog. People keep dogs for many reasons including guarding of property or persons, and historically for fighting. Canine behaviour may be influenced by several factors including genetic predisposition, early socialization and learning, current environment, as well as owner attitudes and training. Certain breeds or lines within breeds have been bred for particular behavioural characteristics; some of these include aggressive behaviour. However, all behaviours are not necessarily uniform within breeds and may or may not be present within individuals. De-sexing, obedience training and/or behaviour modification including psychopharmacotherapy may assist in modifying aggressive behaviour. Veterinarians, breed societies, breeders, welfare agencies, pet shops and owners, should accept their 15 FECAVA NEWS as a WSAVA Member Association to small animal veterinarians around the globe who are striving for practice excellence. which identifies the dog as dangerous. 7. Resale of dangerous dogs should be regulated, policed, and permits issued. WSAVA partners with its Member Associations to share Member Services AAHA Standards of Accreditation to be Available for WSAVA Member Associations The American Animal Hospital Association Standards of Accreditation are recognized around the world as the benchmark for quality care in veterinary medicine. Approximately 3,000 veterinary practices in the U.S. and Canada are accredited by AAHA and adhere to the AAHA Standards. For practices in other countries, these standards provide a framework for reaching new levels of excellence. WSAVA members will be able to view the AAHA Standards by following a link available on the WSAVA Home Page. There are more than 900 AAHA Standards, which cover quality patient care, client service, and staff empowerment and recognition. To view the standards, a user name and password will be required and this is available through your WSAVA member association (to see if your local/national association is a WSAVA member, visit the member association pages of the WSAVA website). So, contact your WSAVA Member Association and tap into this exciting and wonderful resource kindly made available by AAHA • Proceedings Available On-Line Proceedings from the WSAVA/FIAVAC/AMMVEPE 2005 World Congress are now available on-line via the WSAVA website (link on the right-hand column of the Homepage). Contents include Congress abstracts as well as proceedings from more than 250 lectures covering 26 different disciplines by 110 speakers. Most disciplines are covered The proceedings are also available for the animal welfare forum as well as the practice management track and 4 separate State of the Art Lectures (SOTAL) providing cutting-edge information on current topics from world-renowned veterinary scientists. And it’s all just a mouse-click away from the comfort of your own chair! • Future Congresses 31st WSAVA/12th FECAVA/14th Czech Small Animal Veterinary Association Congress, Prague, Czech Republic – October 11-14, 2006. Full details are featured in this and past issues of EJCAP Sydney Convention Centre, Sydney, Australia – August 19-23, 2007 Dublin, Ireland – August, 2008 Sao Paulo, Brazil – 2009 (Specific date to be determined). UEVP NEWS European Union enlargement and UEVP From Christopher Buhot, UEVP President • Continuous Professional Development or Life Long Learning voluntary although highly recommended for veterinarians working in general practice. Making it compulsory without proper policing is of little use. However, 3L for acknowledged or specialized veterinarians should be mandatory in order for them to receive and hold their title. The hours spent on 3L should be noted by veterinarians on their personal record card (probably in the future on a professional ID card).Veterinarians working in general practice should obtain at least 100 scientific meeting attendance hours over 5 years and 100 hours by other forms of 3L, in other words an average of 40 hours yearly. Scientific attendance hours can be obtained by attending national and international 3L courses or congresses, other forms of 3L hours such as by reading articles in national or international veterinary journals, e-learning or self-assesment. 3L scope is not only limited to veterinary medicine and surgery. However, it must be closely linked to the veterinarian’s main activity. It includes all topics relevant and profitable to the practitioner's professional life. 3L courses must be evaluated by the participants, and the evaluation forms should be sent to the National 3L Committee, which it is recommended are set up in each country and will be in charge of accrediting 3L providers and 3L courses and controlling veterinarians’ 3L records. Finally, as we seek harmonisation in the EU, a European 3L committe has been set up. Already The European Coordination Committee for Veterinary Training has already agreed to take over this duty. The R.C.V.S. (Royal College of Veterinary Surgeons – UK statutory body) gives an excellent definition of CPD viz “The systematic maintenance, improvement and broadening of knowledge and skill and the development of personal qualities necessary for the execution of professional and technical duties throughout the veterinarian's working life.” CPD can be regarded as an ethical obligation, and is in full accordance with the FVE Code of Good Veterinary Practice. Following recent meetings in Bologna, it has been decided that the term CPD should be replaced by the name of L.L.L. or 3L which stands for Life Long Learning. At the UEVP Spring General Assembly all delegates adopted the position paper on 3L. It was agreed that a single qualification no longer gives the right to practise for life without competition and control. Practitioners must keep their professional knowledge up to date to provide the best service to their clients and patients. Furthermore, veterinarians have to be able to respond to the increasing demand for the development of advanced scientific skills.The delegates affirmed that we must also keep in mind the possible consequences on professional liability. The assembly felt strongly that the veterinary profession must be in charge of its own 3L in order to control its content and its quality so that our profession does not fall into disrepute. At the moment, UEVP proposes to do all in its power to make 3L 16 REPRINT PAPER (NL) A pplication of honey in the treatment of skin wounds P.A.M. Overgaauw(1) J.Kirpensteijn(2) S U M M A R Y This paper reviews the current knowledge about the use of honey in the treatment of skin wounds. Most experience has been gained in human medicine, but first reports of its use in animals are available. Honey has, after application to wounds, an antibacterial effect against several bacteria and shows reduced oedema and discharge. Moreover, it helps in generating granulation and epithelial tissue and has an odour neutralizing effect. The need to use sterilized honey products free from pesticide and antibiotic residues is explained. INTRODUCTION This paper originally appeared in: Tijdschrift voor Diergeneeskunde* (2005)130, p 115-116 and amoxicillin with clavulanic acid, against the most common skin bacteria. Important in this context is an adequate concentration of active antibiotics in the blood before the wound is operated on. This is best achieved by intravenous administration of the antibiotic just before the induction of anaesthesia. There are no medical grounds for the local application of antibiotics. Anecdotes do exist however, of substances enhancing the wound healing process, such as honey, which has reportedly been used for centuries for its favourable effect on the wound healing process. This effect is explained by the fact that honey has a cleansing effect, absorbs oedema and odours, displays anti-microbial and infection inhibiting effects, and induces granulation, epithelialisation, tissue generation and bloodsupply in the wound area [4,8]. Dog and cat skin wounds are a common occurrence and are brought into vet practices every day. When treating them, both vet and owner often initially apply local medications. There is a preference for “something” to apply on a wound and a number of ointments and creams are marketed for this purpose. They generally are unnecessary and often even counterproductive, as virtually every medication will retard the wound healing process. Recently, however, two medications were reported as being proven to help the wound healing process by local application, i.e. 65% glycerol [12,16] and honey. The latter product is discussed in more detail below. WOUND HEALING ANTIBACTERIAL EFFECT OF HONEY Freshly incurred wounds are best cleansed with a physiological salt solution, and then sutured. Superficial wounds do not require antibiotics when treated properly and where extensive tissue damage is not evident. Only infected, deep wounds require antibiotic treatment [10]. Honey has an antibacterial effect against several bacteria such as Pseudomonas, staphylococci, streptococci and E. coli. Even some antibiotic-resistant bacteria, such as MRSA (Methicillin Resistant Staphylococcus Aureous) and VRE (Vancomycin Resistant Enterococci) are reportedly sensitive [2,3,9]. A This involves the systemic administration, for a minimum of 5 to 7 days, of a broad-spectrum antibiotic such as cephalosporines (1) Certified Veterinary Microbiologist, Certified Parasitologist, Molecaten 57, NL - 3772 LJ Barneveld. E-mail: [email protected] (2) Diplomate of the European and American Colleges of Veterinary Surgery, Department of Companion Animal Medicine, Veterinary Faculty, Utrecht University, Yalelaan 8, NL - 3508 TD Utrecht * Presented by NACAM (The Netherlands) 17 Application of honey in the treatment of skin wounds OTHER EFFECTS OF HONEY Animal experimental research has shown that honey reduces the number of neutrophils cells infiltrating the wound. Clinical studies showed moreover, reduced oedema and discharge. The hyperosmolarity of honey and stimulation of body enzymes induces autolysis of necrotic tissue in a wound, achieving remoral of debris. Honey helps in the generation of granulation and epithelia tissues because hydrogen peroxide stimulates angiogenesis and the growth of fibroblasts. Also, low pH values and enhanced angiogenesis help release oxygen, stimulating tissue regeneration. The odour neutralizing effect is achieved because bacteria in the wound are being inhibited, thus also reducing debris volumes. Also, once the honey has been applied, the bacteria will utilize the sugars it contains. This generates the odourless milk acid [5]. Sutured wound on dog’s paw, Day O. HUMAN AND ANIMAL CLINICAL RESEARCH For skin burns, very good results were found comparing honey treatment to treatment with a silver-sulfadiazin [13] and polyurethane film [14]. The sterile antibacterial wound ointment with a honey basis (50% v/v)*, available in the Netherlands, was used in a multi-centre case-report study of 139 nursing homes and GP practice patients suffering from ulcers, decubital ulcers, abrasions and burns [15]. On several wounds, different wound treatment products were used (e.g. Betadine ointment®, Duoderm®, silver-sulfadiazin) and their effects compared in the same patient. Depending on the type of wound, a 14-47% faster healing process has been reported. However, no statistical analysis of the results was carried out. The specific wound ointment with a honey basis* also showed an anti-fungal effect against Candida albicans. Now, the manufacturer has the first dog and cat case-studies available. Application of sterile honey ointment. NEED FOR AND USE OF STERILE HONEY concentration of 10% v/v is sufficient for full inhibition of wound bacteria [5]. The antibacterial effect is caused, among other things, by hyper-osmosis, low 3.6 pH, and the presence of a thermo unstable substance named inhibine, hydrogen peroxide and enzymes such as catalysts. Hydrogen peroxide is generated, along with glucose acid, from honey as a result of an reaction of the enzyme glucose oxidase (created by the bee) with the glucose. This reaction occurs after the honey has been diluted in the wound. The gradually released hydrogen peroxide has an adverse affect on bacteria but not on the normal cells, thus creating no cellulour damage. The assumption is that also other antibacterial substances also occur, originating from various flowers [17]. Studies show that bacteria display a different sensitivity to monofloral honey from differing species of plants [1,17]. It is evidently an attractive option to use a natural product for the treatment of patients, however one important aspect must be emphasized before problems arise for man and animals. Only a very few studies state that sterile honey was used [14]. This fact is often not stated, or the honey is presumed to be sterile [13]. This however is a major misconception. Honey may contain Bacillus sp. and Clostridium traces and thus cause botulism [6,11]. The use of natural honey on necrotic wounds is therefore contraindicated in such cases counter indicated. Also, honey may contain pesticides as well as antibiotic residues such as tetracyclines used on bees. The recommendation therefore is to use only honey for medical purposes that originates from specific pathogen free (SPF) nonmedicated bees living in areas where no pesticides are in use. Also irradiated honey produces a sterile product, without any * Mesitran®; Klinion® series, Medeco BV (www.medeco.nl). 18 P.A.M. OVERGAAUW J. KIRPENSTEIJN EJCAP - Vol. 16 - Issue 1 - April 2006 [3] COOPER (R.A.), MOLAN (P.C.), HARDING (K.G.) - The sensitivity to honey of Gram-positive cocci of clinical significance isolated from wounds. J Appl Microbiol ,2002, 93: 857-863 [4] EFEM (S.) - Clinical observations of the wound healing properties of honey. Br J Surg 1988, 75: 579-581 [5] EILDERS (M.), ZWAGA (S.) - (Honey, the bee as wound caretater). Pharma Selecta, 2003, 19 : 96-100 [6] MIDURA (T.F.) et al - Isolation of Clostridium botulinum from honey. J Clin Microbiol ,1979, 9: 282-283 [7] MOLAN (P.C.), ALLEN (K.L.) - The effect of gamma-irradiation on the antibacterial activity of honey. J Pharm Pharmacol, 1996, 48: 1206-1209 [8] MOLAN (P.C.) - Potential of honey in the treatment of wounds and burns. Am J Clin Dermatol, 2001, 2: 13-19 [9] NATARAJAN (S.), WILLIAMSON (D.), GREY (J.), HARDING (K.G.), COOPER (R.A.) - Healing of an MRSA-colonized, hydroxyurea-induced leg ulcer with honey. J Dermatol Treat, 2001, 12: 33-36 [10] OVERGAAUW (P.A.M.) - (The treatment of bitewounds in dogs and cats). Diergeneesk Vademecum, 2003, 3 (7): 1-2 [11] POSTMES (Th.), BOGAARD (A.E.A.M.) VAN DEN - Honey for wounds, ulcers, and skin graft preservation. Lancet, 1993, 342: 756-757 [12] RAVISHANKER (R.), BATH (A.S.), ROY (R.) - Amnion Bank the use of long term glycerol preserved amniotic membranes in the management of superficial and superficial partial thickness burns. Burns, 2003 Jun, 29 (4): 369-374 [13] SUBRAHMANYAM (M.) - Topical application of honey in treatment of burns. Br J Surg, 1991, 78: 479-478 [14] SUBRAHMANYAM (M.) - Honey impregnated gauze versus polyurethane film (Opsite®) in the treatment of burns – a prospective randomised study. Br J Plastic Surg ,1993, 46: 322323 [15] VANDEPUTTE (J. L.) - Mesitran clinical reports study. 2002. [16] VLOEMANS (A.F.P.M.), SCHREINEMACHERS (M.C.J.M), MIDDELKOOP (E.), KREIS (R.W.) - The use of glycerolpreserved allografts in the Beverwijk Burn Centre: a retrospective study. Burns, 2002 Oct; 28 Suppl 1: S21-25 [17] WILLIX (D.J.) MOLAN (P.C.), HARFOOT (C.G.) - A comparison of the sensitivity of wound-infecting species of bacteria to the antibacterial activity of manuka honey and other honey. J Appl Bact, 1992, 73: 388-394 Wound on paw after one week of daily treatment. change in properties [7,11]. In the Netherlands, a sterile honey ointment for human use is available in tubes of 20 and 50 g *. The ointment may be used in combination with wound dressings and the product information sheet states that application once a day is sufficient. Scientific research into the wound healing effect of honey in (domesticated) animals has not been performed and this will need to be done in the future to obtain independent proof that honey ointment is a useful addition to the existing treatments of (infected) wounds in veterinary practices (figures 1 and 2). REFERENCES [1] ALLEN (K.L.), MOLAN (P.C.), REID (G.M.) - A survey of the antibacterial activity of some New Zealand honeys. J Pharm Pharmacol. 1991, 43: 817-822 [2] COOPER (R.A.), HALAS (E.), MOLAN (P.C.) - The efficacy of honey in inhibiting strains of Pseudomonas aeruginosa from infected burns. J Burn Care Rehabil, 2002, 23: 366-370 19 REPRINT PAPER (GR) A case of periosteal proliferative polyarthritis in a cat M. Karayannopoulou(1), Z.S. Polizopoulou(2), A.F. Koutinas(3), M.N. Patsikas(1), G. Kazakos(1), A. Fytianou.(2) S U M M A R Y In this paper a case of periosteal proliferative polyarthritis is described in an 11-year old, female Siamese cat, that was admitted to the Surgery Clinic of the Veterinary School, A.U.Th., with a 6-month history of nonweight bearing lameness of the left thoracic limb. At physical examination, restricted range of motion of the left elbow joint, local swelling and pain were detected. In the radiological examination of the affected joint the main finding was an extensive periarticular and irregular periosteal new bone formation. The results of the complete blood count and routine serum biochemistry were within normal limits and the cat was serologically negative for FeLV and FIV. Synovial fluid examination showed a lymphoplasmacytic pleocytosis, while the bacterial culture was negative. Prednisolone given at an anti-inflammatory dose for two consecutive weeks resulted in a marked improvement of the clinical sings. However, two months after the end of the treatment lameness reappeared, but this time in the contralateral thoracic limb, due to the involvement of the same joint. Radiology revealed the same type of lesions in the right elbow joint, while the left became ankylosed. Again, prednisolone given at an immunosuppressive dose for two weeks gave only moderate improvement in both the clinical conditions and the radiological changes in the animal. For this reason azathioprine at the dose of 1 mg/kg BW, every 48 hours, was added to therapy that lasted for 5 months. Transient mild leukopenia, that resolved after decreasing the dose of azathioprine by 25% was the only adverse side effect noticed. At the end of the treatment, regression of the radiographical lesions in both elbows enabled the cat to walk with a stilted gait despite the development of joint ankylosis bilaterally. The disease was kept in remission during the 12-month follow up period. INTRODUCTION Schrader and Sherding 1994, Thomson 1994, Roush 1997, Day 1999, Hay and Manley 2000); however, synovial immune-complex deposition may be involved (Day 1999, Davidson 2002). Joint diseases, similar to feline PPP, have been described in both humans (Reiter’s arthritis) (Bennett and Nash 1988, Goring and Beale 1993, Thompson 1994, Schrader 1995, Pedersen et al 2000) and dogs (Bennett and Nash 1988, Bennett 1990, May and Bennett 1994, Day 1999). In general, the prognosis is guarded to poor, as CPP tends be progressive making euthanasia necessary when the quality of life becomes unacceptable (Day 1999). The purpose of this article is to present the clinical and radiological This paper originally appeared in: The Journal of the Hellenic Veterinary Medical Society* (2004) 55, p 46-54 Periosteal proliferative polyarthritis (PPP) is the most common form of feline chronic progressive polyarthritis (CPP), an uncommon erosive joint disease that was first studied by Pedersen and associates in 1980. Despite its association with FeSFV, FeLV (Pedersen et al 1980, Lipowitz 1985, Schrader 1995, Tizard 2000) or occasionally FIV infection (Taylor 2003), PPP is still considered an immune-mediated disorder, although the precise mechanism that triggers the immunologic reaction remains unknown (Nelson and Couto 1992, Bennett 1994, (1) Clinic of Surgery, (2) Laboratory of Clinical Diagnosis and Clinical Pathology, (3) School of Veterinary Medicine, Clinic of Companion Animal Medicine, A.U.Th. Greece Corresponding author: Z.S. Polizopoulou, 11 St. Voutyra str. ,GR-546 27, Thessaloniki. E-mail: [email protected] * Presented by HVMS (Greece) 21 A case of periosteal proliferative polyarthritis in a cat Subsequently, the cat was put on oral prednisolone (Prezolon®) at the anti-inflammatory dose of 2 mg/kg BW, once daily, for two consecutive weeks which resulted in a marked improvement of the functional state of the affected limb. A gradual tapering of the prednisolone dosage was further suggested, but the owner stopped giving it on his own initiative. findings, as well as the response to treatment of a cat with PPP, which, to our knowledge, has never been reported in the greek literature. CASE DESCRIPTION An 11-year old, female Siamese cat, weighing 6 kg, was admitted to the Surgery Clinic, School of Veterinary Medicine, Aristotle University of Thessaloniki, Greece, with a 6-month progressive and non-weight bearing lameness of the left thoracic limb as the main complaint; no medical treatment, of any kind, had been attempted prior to admission. At physical examination, restricted range of motion of the left elbow joint, local swelling and pain were detected upon palpation. Radiological examination of the affected joint showed excessive periarticular soft tissue radiopacity accompanied by extensive and irregular periosteal new bone formation (figure 1). The other limb joints as well as the thoracic and abdominal cavity and the vertebral column appeared radiographically normal. The results of complete blood count (haematocrit, haemoglobin, leucocyte and platelet counts, differential white blood cell count), routine serum biochemistry (total protein, albumin, ALP, ALT, γ-GT, BUN, creatinine) and FeLV+FIV ELISA serology were found to be within normal limits or negative, respectively. Synovial cytology of the affected joint disclosed the presence of numerous lymphocytes and plasma cells, while the bacterial culture came back negative. Synovial biopsy was also suggested but declined by the owner. Approximately two months after the end of the aforementioned treatment, the cat started limping, but on the right thoracic limb this time. The painful swelling of the ipsilateral elbow joint, along with the already ankylosed left elbow joint, made the cat reluctant to jump and walk. Radiological examination of the right elbow showed the presence of periosteal proliferation at the attachment site of the joint capsule (figure 2); the left elbow lesions were well demarcated and had more regular margins than the first time. Again, the radiographs of the other limb joints did not disclose anything abnormal. Oral prednizolone was re-instituted, but at an immunosuppressive dose this time (4 mg/kg BW, per os, once daily) for two consecutive weeks, tapered gradually over a period of three additional weeks. The radiological examination, at the end of the treatment, revealed that the lesions of the left elbow joint remained unchanged while those of the contralateral joint appeared much worse (figure 3). Thereupon, it was decided to use azathioprine (Azathioprin®), at the dose of 1 mg/kg BW, per os, every 48 hours, along with 1 mg/kg BW prednizolone, every 24 hours, tapered to 0.5 mg/kg BW. This dose was subsequently used along with azathioprine, on an alternate day basis. The combination therapy was administered for a 5-month period, during which the cat was being monitored clinically and clinicopathologically (every 15 days), as well as radiographically (every month). Because of a transient leukopenia (4,900/µl) that appeared approximately one month after the beginning of the treatment, the dose of azathioprine was lowered by 25% until the number of WBC’s was restored to normal range (5,00018,900/µl). The radiological examination of the right elbow showed a substantial regression of the lesions at the end of the Figure 1. Lateral radiograph of the left elbow on the day of first admission, showing the increased radiopacity of the expanded periarticular soft tissues, as well as the extensive periarticular new bone formation Figure 2. Lateral radiograph of the right elbow just before the institution of the immunosuppressive treatment, demonstrating periosteal new bone formation at the attachment site of the joint capsule. 22 M. KARAYANNOPOULOU EJCAP - Vol. 16 - Issue 1 - April 2006 this cat (Pedersen et al 1980, Bennett and Nash 1988, Schrader and Sherding 1994). The typical radiological finding in PPP is a periarticular extensive and profound periosteal proliferation, that ultimately may lead to ankylosis of the affected joint(s) (Bennett and Nash 1988, Nelson and Couto 1992, Schrader and Sherding 1994, De Haan and Beale 1995) and was also noticed in this cat. Subchondral erosions of mild degree, usually located at the margins of the articular cartilage, may also occur in PPP (Bennett and Nash 1988, Bennett 1994, May and Bennett 1994, Schrader and Sherding 1994, Day 1999); but they were not demonstrated in either of the elbow joints of our feline patient, as it has also been reported in other cases (Lipowitz 1985, Nelson and Couto 1992, Goring and Beale 1993, De Haan and Beale 1995, Schrader 1995, Hay and Manley 2000). In the deforming erosive or rheumatoidlike form of feline CPP, subchondral erosions and cysts are quite visible in radiographs and may eventually lead to the subluxation or luxation of the affected joint (Bennett and Nash 1988, Goring and Beale 1993, Schrader and Sherding 1994, Hay and Manley 2000, Pedersen et al 2000, Taylor 2003). Also, the frequently observed deformity and instability of the carpal and other distal joints (Taylor 2003) was not part of the clinical picture in this cat. Since the idiopathic form of feline immune-mediated nonerosive polyarthritis shares some clinical features with PPP, the diagnosis was mainly based on the marked periarticular new bone formation over the affected joints of the cat (Bennett and Nash 1988, Nelson and Couto 1992, Day 1999, Pedersen et al 2000). The same kind of polyarthritis, that appears secondarily to infections, neoplasms, drugs or vaccines (Day 1999, Hay and Manley 2000, Pedersen et al 2000, Taylor 2003), was also excluded from the list of differentials from a historical and clinical standpoint. Systemic lupus erythematosus, an extremely uncommon cause of nonerosive polyarthritis in cats (Bennett and Nash 1988, Pedersen et al 1989) was also ruled out from the beginning because its polysystemic nature did not fit into the clinical picture of this cat. Interestingly, this animal did not exhibit anorexia, fever and / or peripheral lymphadenopathy, which are, at least initially, common manifestations in PPP, (Pedersen et al 2000, Taylor 2003). This could be explained by the delayed first admission of the animal, although these symptoms were not manifested on the second admission, as well. Figure 3. Lateral radiograph of the right elbow after the immunosuppressive treatment with prednisolone, showing the worsening of the periarticular new bony tissue formation. treatment period (figure 4a). At the same time, a decreased radiopacity of the periarticular new bony tissue in the left elbow was clearly visible (figure 4b). In spite of the fact that ankylosis was well established in both elbow joints, the absence of pain enabled the cat to walk with a stilted gait. The clinical condition of the animal remained unchanged within the 12-month followup period, whereas the lesions did not deteriorate further in the left and improved moderately in the right elbow joint. DISCUSSION PPP occurs exclusively in intact or neutered male adult cats, regardless of their breed (Pedersen et al 1980, Moise and Crissman 1982, Bennett and Nash 1988, Schrader and Sherding 1994, Roush 1997, Pedersen et al 2000). The appearance of PPP in female or elderly patients, like the cat of our report, is only seldom witnessed (Pedersen et al 1980, Bennett and Nash 1988). The disease in this cat was not associated with either FeLV or FIV infection, which have not been proven to cause PPP, at least experimentally (Taylor 2003). Synovial fluid testing for FeSFV was not considered necessary because the virus has been isolated from either the affected or normal feline joints (Day 1999). Lesions tend to have a symmetrical distribution, with the carpal and tarsal joints being more frequently affected compared to the stifle, shoulder, hip or the elbow joint, as was the case in In the erosive types of feline polyarthritis the continual assessment of the animals is important because the true nature of the disease may only become apparent as it progresses, while certain individual factors will decide how it will be finally manifested (Bennett 1995). Since the radiographic changes (periosteal new bone formation, cyst-like metaphyseal defects, destruction of articular cartilage, subchondral bone development) in both the bacterial L-form and mycoplasmal (Mycoplasma gatae, Mycoplasma felis) polyarthritis are similar to those of PPP (Carro 1994, Schrader and Sherding 1994) these differentials should have also been pursued diagnostically. However, these wall-less and prokaryotic bacteria necessitate the use of specific media to grow (Carro et al. 1989), which 23 A case of periosteal proliferative polyarthritis in a cat a b Figure 4. Lateral radiograph of the right (a) and the left (b) elbow, immediately after the end of the 5-month immunosuppressive therapy with azathioprine and prednisolone, showing substantial regression (a) and decreased radiopacity (b) of the periarticular new bony tissue. unfortunately were not available. Since these bacterial infections cannot be excluded on clinical and radiological grounds alone, tetracyclines, lincomycin and tylosin (Carro et al. 1989) should have been tried prior to institution of the immunosuppressive treatment. of glucocorticosteroids (Beale 1988, May and Bennett 1994, Hay and Manley 2000, Pedersen et al 2000, Tizard 2000). The use of azathioprine in cats is reportedly associated with a life-threatening leukopenia and thrombocytopenia (Beale 1990, Beale et al 1992, Plumb 1999, Scott et al 2001), that could be attributed to the low erythrocyte thiopurine methyltransferase activity in this animal species (Foster et al 2000, Papich 2000, White et al 2000). Lower doses of azathioprine, such as 0.3 mg/kg BW, once daily (Papich 2000), 0.3-0.5 mg/kg BW every 48 hours (Birchard and Sherding 2000) or 1.5-3.125 mg/cat every 48 hours (Papich 1995), are thought to be relatively safer. The dose of 1 mg/kg BW every 48 hours, that was used in this cat, has also been recommended, provided that a close monitoring for early detection of side effects is regularly pursued (Plumb 1999, Pedersen et al 2000, Boothe and Mealey 2001); however even this dose is still considered unacceptably high (Papich 2000). Periarticular exostoses in hypervitaminosis A, that may also lead to lameness, are very similar to those of PPP, but the dietary history (commercial cat food) of the cat ruled-out this possibility (Bennett 1994, Schrader and Sherding 1994, Harari 1997, Johnson and Watson 2000); furthermore, no exostoses could be seen in the radiographs of the cervical spinal column (Bennett 1994, Harari 1997, Johnson and Watson 2000). In PPP, lifelong immunosuppressive therapy is often required in an attempt to halt the progression of the lesions and to obtain clinical remission, because in the majority of cases the clinical signs relapse when there is a decrease of the dosage or no medication at all (Schrader and Sherding 1994, Day 1999, Pedersen et al 2000, Taylor 2003). In this cat, the initial use of prednisolone at an antiinflammatory dose could be justified by the one joint involvement of the lesions, which made the diagnosis of PPP uncertain. The clinical improvement, noticed initially, would have been more prolonged had the owner complied with the full course of treatment. The recurrence of clinical signs in both frontlimbs made the diagnosis of PPP more certain and, therefore, the use of prednisolone at immunosuppressive dosage necessary. Azathioprine had to be added subsequently, because of the aggravation of the right elbow lesions, along with the development of ankylosis in the contralateral joint. Combination immunosuppressive therapy is recommended in small animal immune-mediated arthritides, not only for the achievement of longer remission periods, but to lower the risk of side effects that are associated with the prolonged use Since azathioprine is generally considered unsafe for the cat (Bennett 1995, Papich 2000, Taylor 2003) it is strongly advised to use cyclophosphamide or chlorambucil instead, along with prednisolone at low immunosuppressive dosage (Taylor 2003). Combination therapy with the use of prednisolone, azathioprine (7.5 mg/cat every 48 hours) and cyclophosphamide was applied in 5 CPP cats with moderate to poor results (Pedersen et al 1980). In the same study, two of the treated animals died of druginduced side effects, although the detrimental role of azathioprine could not be assessed. Transient leukopenia, that was also noticed in our feline patient at the 16th azathioprine administration, subsided when its dose was lowered by 25%. When a similar dosage (1.1 mg/kg BW, every 48 hours) was used in 8 cases of feline pemphigus foliaceus, 4 of these cats developed leukopenia after the 8th administration (Caciolo et al 24 M. KARAYANNOPOULOU EJCAP - Vol. 16 - Issue 1 - April 2006 methyltransferase activity in the erythrocytes of cats. J Vet Intern Med, 14: 552-554 GORING (R.L.), BEALE (B.S.) (1993) - Immune-mediated arthropathies. In: Disease Mechanisms in Small Animal Surgery. 2nd ed, Lea and Febiger, Philadelphia: 742-757 HARARI (J.) (1997) - Diseases of bone. In: Handbook of Small Animal Practice. 3rd ed, WB Saunders Company, Philadelphia: 830-845 HAY (C.W.), MANLEY (P.A.) (2000) - Immune-mediated arthritis. In: Manual of Small Animal Practice. 2nd ed, WB Saunders Company, Philadelphia: 1228-1232 JOHNSON (K.A.), WATSON (A.D.J.) (2000) - Skeletal diseases. In: Textbook of Veterinary Internal Medicine. 5th ed, WB Saunders Company, Philadelphia: 1887-1916 LIPOWITZ (A.J.) (1985) - Immune-mediated arthropathies. In: Textbook of Small Animal Orthopedics. JB Lippincott Company, Philadelphia: 1055-1077 MAY (C.), BENNETT (D.) (1994) - Immune mediated arthritides. In: Manual of Small Animal Arthrology. BSAVA, Cheltenham: 8699 MOISE (N.S.), CHRISSMAN (J.W). (1982) - Chronic progressive polyarthritis in a cat. J Am Anim Hosp Assoc, 18:965-969 NELSON (R.W.), COUTO (C.G.) (1992) - Disorders of the joints. In: Essentials of Small Animal Internal Medicine. Mosby-Year Book Inc, St Louis, Missouri: 820-828 PAPICH (M.G.) (1995) - Table of common drugs: approximate dosages. In: Kirk’s Current Veterinary Therapy XII Small Animal Practice. WB Saunders Company, Philadelphia: 1429-1430 PAPICH (M.G.) (2000) - Handbook of Veterinary Drugs. WB Saunders Company, Philadelphia: 43-44 PEDERSEN (N.C.), POOL (R.C.), O’BRIEN (T). (1980) - Feline chronic progressive polyarthritis. Am J Vet Res, 41: 522-535 PEDERSEN (N.C.), WIND (A.), MORGAN( J.P.), POOL (R.R). (1989) - Joint diseases of dogs and cats. In: Textbook of Veterinary Internal Medicine. 3rd ed, WB Saunders Company, Philadelphia: 2329-2377 PEDERSEN (N.C.), MORGAN (J.P.), VASSEUR (P.B.) (2000) - Joint diseases of dogs and cats. In: Textbook of Veterinary Internal Medicine. 5th ed, WB Saunders Company, Philadelphia: 18621886 PLUMB (D.C.) (1999) - Veterinary Drug Handbook. 3rd ed, Iowa State University Press, Ames: 71-73 ROUSH (J.K.) (1997) - Diseases of the joints and ligaments. In: Handbook of Small Animal Practice. 3rd ed, WB Saunders Company, Philadelphia: 813-829 SCHRADER (S.C.) (1995) - Joint diseases of the dog and cat. In: Small Animal Orthopedics, Mosby-Year Book Inc, St Louis, Missouri: 437-471 SCHRADER (S.C.), SHERDING (R.G.) (1994) - Disorders of the skeletal system. In: Diseases and Clinical Management. 2nd ed, Churchill Livingstone Inc, New York: 1599-1647 SCOTT (D.W.), MILLER (W.H.), GRIFFIN (C.E.) (2001) - Immunemediated diseases. In: Muller and Kirk’s Small Animal Dermatology. 6th ed, WB Saunders Company, Philadelphia: 667-779 TAYLOR (S.M.) (2003) - Joint disorders. In: Small Animal Internal Medicine. 3rd ed, Mosby Inc, St Louis, Missouri: 1079-1092 TIZZARD (I.R.) (2000) - Veterinary Immunology. 6th ed, WB Saunders Company, Philadelphia: 391-395 WHITE (S.D.), ROSYCHUK (R.A.W.), OUTERBRIDGE (C.A.), FIESELER (K.V.), SPIER (S.), IHRKE (P.J.), CHAPMAN (P.L.) (2000) - Thiopurine methyltransferase in red blood cells of dogs, cats and horses. J Vet Intern Med, 14: 499-502 WILKINSON (G.T.), ROBINS (G.M.) (1979) - Chronic progressive polyarthritis in a cat. J Small Anim Pract, 20: 293-297 1984), while doses twice as high (2.2 mg/kg BW, every 48 hours) led to severe leukopenia (<3000 leukocytes/µl) after approximately 1.5 months of continuous administration (Beale 1992). The absence of life-threatening side effects in our feline patient, even after the 5-month treatment period, may indicate that this dose can be tolerated can be tolerated, at least by some cats. Interestingly, the higher degree of periosteal bony tissue regression in the right elbow joint, where the immunosuppressive treatment started as early as two weeks after the appearance of the clinical signs, indicates that its early application is associated with a better outcome (Wilkinson and Robins 1979, Schrader and Sherding 1994). REFERENCES BEALE (K.M.) (1988) - Azathioprine for treatment of immunemediated diseases of dogs and cats. J Am Vet Med Assoc, 192: 1316-1318 Beale (K.M.) (1990) - Azathioprine toxicity in the domestic cat. In: Advances in Veterinary Dermatology, Proceedings of the First World Congress of Veterinary Dermatology, Dijon, France, September 1989. WB Saunders Company, London: 457-458 BEALE (K.M.), ALTMAN (D.), CLEMMONS (R.R.), BOLON (B.) (1992) - Systemic toxicosis associated with azathioprine administration in domestic cats. Am J Vet Res, 53: 1236-1240 BENNETT (D.) (1990) - Joints and joint diseases. In: Canine Orthopedics. 2nd ed, Lea and Febiger, Philadelphia: 761-853 Bennett (D.) (1994) - The musculoskeletal system. In: Feline Medicine and Therapeutics. 2nd ed, Blackwell Scientific Publications, Oxford: 132-191 BENNETT (D.) (1995) - Treatment of the immune-based inflammatory arthropathies of the dog and cat. In: Kirk’s Current Veterinary Therapy XII Small Animal Practice. WB Saunders Company, Philadelphia: 1188-1195 BENNETT (D.), NASH (A.S.) (1988) - Feline immune-based polyarthritis: a study of thirty-one cases. J Small Anim Pract, 29: 501-523 BIRCHARD (S.J.), SHERDING (R.G.) (2000) - Manual of Small Animal Practice. 2nd ed, WB Saunders Company, Philadelphia: 1570 BOOTHE (D.M.), MEALEY (K.A.) (2001) - Glucocorticoid therapy in the dog and cat. In: Small Animal Pharmacology and Therapeutics. WB Saunders Company, Philadelphia: 313-329 CACIOLO (P.L.), NESBITT (G.H.), HURVITZ (A.I.) (1984) Pemphigus foliaceus in eight cats and results of induction therapy using azathioprine. J Am Anim Hosp Assoc, 20: 571-577 CARRO (T.) (1994) - Polyarthritis in cats. Compend Contin Educ Pract Vet, 16: 57-67 CARRO (T.), PEDERSEN (N.C.), BEAMAN (B.L.), MUNN (R.) (1989) - Subcutaneous abscesses and arthritis caused by a probable bacterial L-form in cats. J Am Vet Med Assoc, 194: 1583-1588 DAVIDSON (A.P). (2002) - Immune-mediated polyarthritis. In: Textbook of Small Animal Surgery. 3rd ed, WB Saunders Company, Philadelphia: 2246-2250 DAY (M.J.) (1999) - Immunology of the Dog and Cat. Manson Publishing Ltd, London: 133-140 DE HAAN (J.J.), BEALE (B.S.) (1995) - The skeletal system. In: Geriatrics and Gerontology of the Dog and Cat. WB Saunders Company, Philadelphia: 291-312 FOSTER (A.P.), SHAW (S.E.), DULEY (J.A.), SHOBOWALE-BAKRE (E.), HARBOUR (D.A.) (2000) - Demonstration of thiopurine 25 REPRINT PAPER (HILL’S) P utting theory into practice - best practice management for osteoarthritis Stuart Carmichael(1) I N T R O D U C T I O N Osteoarthritis (OA) is an insidiously progressive disease producing pain and loss of function in affected joints. The suffering and restrictions on exercise that the active disease produces, make a profound impact on the quality of life of the patient. Fortunately, although the disease is widespread, estimated to affect one in five of all dogs, it is not always associated with debilitating disease [1]. Indeed it has been speculated that only animals with moderate to severe OA pathology are identified and presented as clinical problems [2]. These facts set the scene for any discussions aimed at identifying management strategies for the disease. OBJECTIVES OF OSTEOARTHRITIS MANAGEMENT This paper is based on a lecture given at the Hill’s European Symposium on Osteoarthritis and Joint Health* clinical problem in an osteoarthric joint [6]. Radiography is vital to confirm the existence of disease in a joint and to eliminate other possible causes of clinical signs (Figure 1). It should not be used to estimate the clinical severity of the condition. Many of the signs accompanying OA are caused by pain and evaluation of this is best achieved by observation and clinical assessment. The classical signs are listed in Table 1. It is the appearance and identification of these signs and how obvious they are that guides the clinician to judge the severity of the disease. These are also used to judge the effectiveness of any management strategy employed. Increasingly, alterations of behaviour indicative of chronic pain are also being assessed as more subtle indicators of an ongoing problem [7]. Assessment of patient behaviour is difficult in the consulting room and relies on the observational skills of the owner (figure 2). In studies attempting to evaluate the accuracy of these owner observations, they were found to compare very favourably with objective assessment of disability provided by force plate measurements on the same animals [8, 9]. This information is extremely useful to allow construction of plans to assist measures to alleviate the consequences of the disease. The goals for management of OA can be identified in global terms as [3, 4] 1. Controlling Pain 2. Maintaining and improving the range of movement and stability of affected joints 3. Limiting functional impairment of the patient These general objectives should underpin any attempts at management. OA is a complex disease and a very clear understanding of the disease process is essential to advise selection of treatment. It has been suggested that best results in human patients are obtained by an individualised and patientcentred approach involving multiple strategies [5]. It would appear that management of the condition in animals is no different. This type of approach delivers the necessary focus to sustain successful management of any affected patient through meeting long-term requirements. RECOGNISING OSTEOARTHRITIS AS A PROBLEM OSTEOARTHRITIS AS A CHRONIC DISEASE The simplest method of recognition is by radiographic review; however there is poor correlation between radiographic appearance and the extent or even existence of a significant It is worth considering the consequences of the chronic nature of OA and how this impacts on the disease itself and any (1) Faculty of Veterinary Medicine University of Glasgow, Bearsden Road, Glasgow, GB-G611QH. E-mail: [email protected] * The lecture on which this paper was based was given at the 9th Annual Hill’s Symposium held in Genova 25th-27th April 2005. Stuart Carmichael is Professor of Veterinary Clinical Studies in the Faculty of Veterinary Medicine at the Glasgow University Veterinary School 27 Putting theory into practice - best practice management for osteoarthritis AIMS OF MANAGEMENT OA is a dynamic condition in which a number of different clinical phases can be recognised (Figure 3). Three clearly recognisable phases are ‘Chronic Phase Silent Disease’, ‘Chronic Phase Active Disease’ and ‘End Stage Disease’. The phase will be determined by the pathological changes already present within the joint and the pain that the animal is experiencing. Several examinations conducted at different time intervals are necessary properly to establish this judging the success or failure of different control measures. Looking at this model (Figure 3) there is a gradual deterioration of the affected joint to end stage disease. The clinical picture may be punctuated by periods of ‘active’ disease, where clinical signs are apparent, and ‘silent’ disease, where there are few or no clinical signs and no pain. Using this judgement the initial aim Figure 1. Hip Radiograph. Radiographic features of OA can be distinctive but are not closely related to function. attempts at treatment. OA remains a slowly progressive condition fuelled by constant release of inflammatory mediators from a chronic low grade inflammatory reaction. Constant stimulation of nociceptive receptors in affected joints can lead to an altered perception of pain with hypersensitivity, hyperalgesia, allodynia and genetic alteration in central transmission pathways to enhance pain sensation. [10, 11] This means that small or even normal stimuli such as normal joint movement can be perceived as painful as a result of physiological re-programming. This can be a very difficult state to reverse once well established. The other, more obvious, consequence of chronic joint debility and inflammation is the increasing involvement of the structures surrounding the joint, producing a much more complex pathological equation. Muscles will atrophy very rapidly as a result of lack of activity and reflex neurogenic feedback stimulated by intra-articular pain. Muscles can suffer focal damage with mediator release and so become a source of diffuse, poorly localised pain. Muscle wastage can also increase problems and pain in the joint by reducing protective support. Changes in subchondral bone can also result in increased pain [12]. Fibrous thickening of joint capsule, ligaments and tendons can accompany muscle wastage. Fibrosis and changes in joint shape caused by new bone formation will produce stiffness and alter joint movement. All of these events add to the cyclic deterioration of the osteoarthritic joint but also create an urgent need for early intervention to avoid escalation of the pathology and so maintain reversibility of clinical signs. The more advanced the condition the more difficult it is to treat. Lameness Stiffness Reduced movement in joint Reluctance or difficulty with exercise Figure 2. Great Dane with OA. Aged behaviour can be a result of chronic pain due to an underlying osteoarthritis problem. of management will be to try to convert active joints to clinically silent phase where signs are minimal. The second aim will be to keep them in this state. The third aim will be to slow the progression along the horizontal axis to end stage disease. OPTIONS FOR THE MANAGEMENT OF OSTEOARTHRITIS There are a number of methods that have been used in the past to good effect and continue to be the main components of any strategy designed to reduce the effects of osteoarthritis in a patient. These can be placed in broad groups as follows 1. Non-pharmacological methods 2. Pharmacological or Medical methods 3. Surgical Interventions Crepitus Swollen joints Muscle atrophy The majority of animals with clinical OA are managed without surgery, but surgery can be the best option depending on the joint involved (hips) and state of pathology. Euthanasia is an option which must be considered in intractable cases. Table 1. Classical signs of osteoarthritis. 28 STUART CARMICHAEL EJCAP - Vol. 16 - Issue 1 - April 2006 MANAGEMENT PLANS FOR OSTEOARTHRITIS Clinical Assessment Assessment o off OA OA Chronic Active Acute The whole process of managing osteoarthritis can be summarised as follows 1. Identification of a problem 2. Assessment of the problem 3. Review possibilities and select an intervention strategy 4. Assess success of this within a set time frame 5. Continue, modify, replace or add to intervention(s) 6. Re-assess etc. (maintenance phase) End Stage Stage Chronic Silent The process must be simple to use, successful in achieving rapid success, sustainable long term and must bring the clinical problem under the control of all concerned. It must also be practical to use and economically feasible. One way of ensuring that there is a controlled approach to the problem is by using pre-determined management plans, which are customised for each patient. These have the multimodal approach embedded but require judgements to be made about priorities for treatment. They often combine pharmacological and non-pharmacological methods and, if properly designed, will evolve to meet the changing needs of a chronic disease process. This last point provides sustainability. Successful plans depend on good quality assessments being made at different times during the management process. These Figure 3. Phases of osteoarthritis. Non-pharmacological methods Non-pharmacological methods can be divided into 1) dietary restriction or manipulation, often to achieve weight loss, 2) instructions about mobility including warm-up exercises, exercise plans, physiotherapy and hydrotherapy, and 3) a third group concerned with mechanical aids to assist or facilitate movement and common sense measures to minimise discomfort. The application of these methods, with the possible exception of dietary intervention to lose weight (Figure 4), is often haphazard and poorly maintained in the animal population. Pharmacological methods The main group of medical agents used to gain control of the signs of OA are the Non-steroidal anti-inflammatory drugs (NSAIDs). These inhibit the cyclo-oxgenase enzyme, which is a key component in the arachidonic acid cycle of inflammation. In the management of human OA, NSAIDs are widely used and are the most frequently requested by arthritis sufferers. We are very fortunate to have a range of reliable and relatively safe NSAIDs licensed for use in dogs. As such, many strategies for OA management centre on these agents. As toxicity is a significant risk with NSAIDs strategies have to be constructed around avoiding toxic side-effects. Other medical agents used include corticosteroids, again for anti-inflammatory effects, and opioids for pain relief. There has been an increasing trend to identifying and employing agents which may modify the articular cartilage, synovial fluid and synovium of affected joints. These are often classed as ‘Slow Acting Drugs’ for OA or ‘Disease Modifying Agents’. Included in this group are parenterally administered polysulphated glycosaminoglycans (PSGAG), pentosan polysulphate and hyaluronic acid. The biggest group of agents in the group are the orally administered so-called ‘nutraceuticals’, including glucosamine and chondroitin sulphate. There are numerous commercially available products containing these agents alone or in combination. These are often used in combination with NSAID medication. The main problem in arthritis management is processing all of the choices available and selecting an appropriate agent to meet the objectives. Many attempts at management are based around a single drug strategy. This contradicts the evidence of the effectiveness of a multimodal approach suggested previously. Figure 4. Bull mastiff with OA. Weight loss in obese animals is a key requisite in any management plan. 29 Putting theory into practice - best practice management for osteoarthritis Primary Secondary Tertiary A Analgesia NSAID Other medical strategies, anti-depressants, relaxants B Bodyweight C Complications Comfort Dietary Control Screen blood Special bed D Disease Joint mobility Nutraceuticals Directed exercise Opiates Acupuncture Specific diets, Hydrotherapy Further medication High surveillance Mobility aids Intra-articular therapy Hydrotherapy E Exercise Touch therapy, heat, massage Modification or salvage surgery Physical therapy Table 2. Management plan options. Applying these options allows complex plans to be constructed which may be necessary in the management of ongoing complex cases. A Analgesia B Bodyweight C Complications Comfort D Disease E Exercise First Visit Second Visit Third Visit NSAID started at maintenance dose BCS 5 Targets set Diet provided Bloods normal Urine normal Special bed Nutraceuticals started Exercise chart position 5 Warm up exercises NSAID dose reduced Every other day NSAID BCS 4 Diet continued Hydrotherapy BCS 3 Maintenance diet Urine Touch therapy institiuted Continue Exercise chart position 4 Ramp for car Radiograph joint, Nutraceuticals Exercise chart position 2 Table 3. Maintenance plan and records. This scheme allows complex plans to be constructed which may be necessary in the management of ongoing complex cases. BCS = body condition score using a five point scale. must be repeatable and allow comparison, not only with the last assessment, but with all assessments recorded. This is the key to exerting control over chronic evolving disease processes. Records must be reliable and assessment easy to do, but also able to detect variations in the clinical state. Assessment of a complex disease like OA is not an easy feat and is by necessity largely subjective. Measuring pain and quality of life is much more difficult than evaluating range of movement and force plate measured weight bearing. Many attempts have been made to construct a scale that can be used to give repeatable measurements of pain with limited success. Carefully constructed client questionnaires seem to be the most useful way of judging the subtle changes that can indicate early improvement or deterioration. early identification of developing problems and rapid adjustment of the plan. The approach is particularly useful in ensuring that non-pharmacological measures are being maintained and optimised. In many cases veterinary nurses can manage a large component of the maintenance phase. PROPOSED MANAGEMENT STRATEGY FOR OSTEOARTHRITIS A ‘Five-Point Plan’ for OA management is proposed to satisfy the requirements outlined above. The plan identifies five separate areas of management which can be addressed simultaneously to deliver a multimodal approach. These areas are analgesia, bodyweight, complications and care, disease and exercise (Table 2). One area should be identified as a priority at the stage of the disease. The plan simplifies the process by providing prepared options in each area and tracking these over time (Table 3). It is supported by feed charts, body condition score information and exercise charts as part of this preparation. Exercise charts, with a number of different levels of exercise clearly explained, are a great time saver and aid to compliance with these plans. The key features can be listed hereafter: Maintenance and management plans A critical way in which the approach to the OA patient can be improved is to develop a maintenance approach and include it in the plan. Regular visits at set times should be arranged for the animal to be checked rather than the animal only being presented when a problem occurs. These are initiated once the presenting signs are brought under control and the plan evolves to concentrate on the long term management issues. This approach is particularly useful in chronic diseases where regular assessments can be used to map gradual progress. It also allows 30 STUART CARMICHAEL EJCAP - Vol. 16 - Issue 1 - April 2006 [6] DIEPPE (P.A.), CUSHNAGHAN (J.), SHEPSTONE (L.) - The Bristol OA500 study progression of osteoarthritis (OA) over 3 years and the relationship between clinical and radiographic features at the knee joint. Osteoarthritis and Cartilage, 1997, 5: 87-97. [7] WEISMAN (M.L.), NOLAN (A.M.), REID (J.) - et al. Preliminary study on owner reported behaviour changes associated with chronic pain in dogs Vet Rec, 2001, 149: 423-424. [8] VASSEUR (P.B.), JOHNSON(A.L.), BUDSBERG (S.C.) - et al. Randomised, controlled trial of the efficacy of carprofen, a non-steroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. JAVMA, 1995, 206: 807-811. [9] HIELM-BJORKMAN (A.K.), KUUSELA (E.), LINMAN (A.), et al. - Evaluation of methods of assessment of pain associated with chronic osteoarthritis in dogs. JAVMA, 2003, 222: 1552-1558. [10] MUIR (W.W.), WOOLF (C.J.) - Mechanisms of pain and their therapeutic implications. JAVMA, 2001, 219: 1346-1356. [11] POCKETT (S.) - Spinal cord synaptic plasticity and chronic pain. Anaesth Analg, 1995, 80: 173-179. [12] ARNOLDI (C.C.), DJURHUUS (J.C.), HEERFORDT (J.), et al. Interosseous phlebography, intraosseous pressure measurements and 99mTc polyphosphate scintigraphy in patients with painful conditions in the hip and knee. Acta Orthopaedica Scandinavica, 1980, 51: 19-28. – It allows a multimodal plan to be set-up and implemented very easily – All of the practice members are working from the same strategy – Different members of the team may have different roles to play – The owner can be informed and instructed easily – Evolution of care progresses with the changing disease requirements – Complex problems can be managed by extending into the secondary or tertiary options identified for each problem whilst still following the strategy. These may be nonresponsive cases or cases with intercurrent disease (hepatic, renal etc.) – It allows incorporation of new developments without altering the basic planning process. Assessment sheets will be analysed to give a specific and global view of the progress over time. In this way a highly focused and sophisticated plan can be used and maintained with the minimum of effort but to the maximum benefit of the affected animal and owner. Best practice can be easily delivered within realistic financial targets. REFERENCES [1] [2] [3] [4] [5] JOHNSON (J.A.), AUSTIN (C.), BREUER (G.J.) et al. - Incidence of canine appendicular musculoskeletal disorders in 16 veterinary teaching hospitals from 1980-1989. VCOT, 1994, 7: 56-69. FOX (S.M.) - Pathophysiology of Osteoarthritic Pain. In: Proceedings of 1st World Orthopaedic Veterinary Congress, Munich 2002: 85-87. ALTMAN (R.D.), HOCHBERG (M.C.), MOSKOWITZ (R.W.), et al. - Recommendations for the medical management of osteoarthritis of the hip and knee Arthritis Rheum, 2000, 19051915. PENDLETON (A.), ARDEN (N.), DOUGADOS (M.), et al. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT) Ann Rheum Dis, 2000, 59: 936-944. GRAINGER (R.), CICUTTINI (F.M.) - Medical management of osteoarthritis of the knee and hip joints. MJA, 2004, 180: 232236 NOTES FOR CONTRIBUTORS TO EJCAP Information relating to material to be directly submitted for Publication in EJCAP can be found as follows: • FECAVA WEBSITE www.fecava.org • IN EJCAP EJCAP 15(1) p65 31 REPRINT PAPER (UK) C anine inflammatory bowel disease: retrospective analysis of diagnosis and outcome in 80 cases (1995-2002) M. Craven(1), J. W. Simpson(1), A. E. Ridyard(1), M. L. Chandler(1) S U M M A R Y The case records of 80 dogs in which idiopathic inflammatory bowel disease (IBD) had been diagnosed were reviewed, and owners were contacted for follow-up information using a telephone questionnaire. The types of IBD encountered were lymphocytic (n=6), lymphocytic-plasmacytic (n=38), eosinophilic (n=6) and mixed inflammation (n=30). Prednisolone, sulphasalazine, metronidazole and tylosin were the most frequently prescribed medications. At follow-up, 21 dogs (26 per cent) were classified as being in remission (for a median of 14 months), 40 dogs (50 per cent) had intermittent clinical signs (for a median of 17 months) and three dogs (4 per cent) had uncontrolled disease (for a median of 19 months). Ten dogs (13 per cent) had been euthanased due to refractory IBD and four of these had entered remission for a median of 21 months prior to developing severe relapse and refractoriness to further treatment. Six dogs (8 per cent) had been euthanased or had died for reasons unrelated to IBD. Hypoalbuminaemia at the time of diagnosis was significantly associated with a negative outcome (P=0.0007). No association was found between the site (P=0.75), type (P=0.44) and severity (P=0.75) of disease. Dietary change to single protein and carbohydrate commercial diets had no association with outcome (P=0.12). Owner assessment of quality of life at follow-up was significantly associated with outcome (P=0.006). INTRODUCTION immune response to a commensal bacterium; and an infection with a pathogenic organism that either remains in the tissues resulting in chronic inflammation, or creates ongoing dysregulation of the immune response after resolution of infection (Hendrickson and others 2002). Recent advances in human medicine also point to the significance of genetic factors in the predisposition, modulation and perpetuation of IBD (Ardizzone and Porro 2002). This paper originally appeared in: The Journal of Small Animal Practice* (2004) 45, p.336–342 The term ‘inflammatory bowel disease’ (IBD) is applied in veterinary medicine to idiopathic inflammation arising from any area of the gastrointestinal tract (Jergens and others 1992). The predominant types of IBD described in dogs are lymphocytic-plasmacytic, eosinophilic and granulomatous (Jacobs and others 1990, Jergens and others 1992). Crohn’s disease and ulcerative colitis are the main forms of IBD in humans, and they are both characterised by a chronic, intermittent or continuous course. Several theories exist about the pathogenesis of IBD in humans including: an autoimmune response to a luminal or mucosal antigen; a dysfunctional It is widely recognised that canine IBD behaves in a similar manner and animal models of disease have been demonstrated to share some of the pathophysiological features of human IBD. For example, the role of CD4+ T cells, tumour necrosis factor (1) 4 Hurdles Way, Duxford, Cambridge GB - CB24PA E-mail: [email protected]. * Presented by BSAVA (UK) 33 Canine inflammatory bowel disease Feature Human IBD Canine IBD Site of inflammation Transmural in Crohn’s disease Mucosal in ulcerative colitis Segmental disease occurs Arthritis, arthralgias, renal disease, pyrexia, mucocutaneous lesions, heptobiliary disease, ophthalmologic complications, osteopenia Surgical, medical Intestinal fistulae, strictures, perianal tags, anal fissures, intramural abscessation, intestinal obstruction, intestinal perforation Worse for Crohn’s disease Lymphoid malignancies Myeloid malignancies Intestinal adenocarcinoma 75 to 85 per cent first remission 50 to 75 per cent first relapse Mucosal Extraintestinal manifestations of disease Treatment modalities Complications Prognosis Neoplastic transformation Remission rates Relapse rates ? Thrombocytopenia Medical Rare ? Worse for eosinophilic disease Not reported Not reported Not reported Table 1. Comparative features of human and canine inflammatory bowel disease (IBD) and interleukin (IL)-12 in mediating intestinal inflammation and the response to antigens derived from commensal bacteria (Hendrickson and others 2002, German and others 2003). Some of the comparative features of canine and human IBD are shown in Table 1. maintenance therapy than induction of remission (Thompson 1991). A definitive association exists between human IBD and later development of intestinal neoplasia, for both Crohn’s disease and ulcerative colitis (Ribeiro and others 1996, van Hogezand and others 2002), but this concept has not been explored in dogs. In contrast to humans, there exists a relative sparsity of information in the veterinary literature regarding the long term disease outcome (Churcher and Watson 1997, Stokes and others 2001). The anatomical site of disease is known to have prognostic significance in human IBD. Patients with Crohn’s ileocolitis are reported to have a greater number of relapses than those with ileitis or colitis alone (Wright 1992). In ulcerative colitis, the greater the extent of colon involved, the more frequent and serious the complications (Sales and Kirsner 1983). The importance of the anatomical site of disease in canine IBD is unknown. The aims of this study were to describe the clinical aspects, treatment, quality of life and long term outcome of canine idiopathic IBD. The site of disease, histopathological type, severity of disease, duration of clinical signs prior to treatment and serum protein status were assessed for use as prognostic indicators. Aspects of drug treatment and diet were also compared with disease outcome. Disease type has also been demonstrated to have prognostic value in humans, ulcerative colitis generally having a more favourable prognosis than Crohn’s disease (Moum 2000, Witte and others 2000). Prognostic significance has been attached to the histopathological type of canine IBD, in that eosinophilic enteritis has been associated anecdotally with common recurrence and a guarded prognosis (Hall and Simpson 2000). MATERIALS AND METHODS The treatment of canine IBD is largely empirical due to the poor understanding of aetiopathogenesis and lack of therapeutic trials. Human clinical trials are numerous (Brignola and others 1992, Elton and Hanauer 1996, Stein and Lichtenstein 2001) and conventional treatment strategies for canine disease have been based upon extrapolation of human research. Corticosteroids, sulphasalazine, azathioprine, antibiotics and dietary trials are currently the mainstay of treatment for all histological types of human IBD, either singly or in combination. The efficacy of such therapeutics in canine IBD has not been determined, and there is no discrimination between drugs prescribed for either induction or maintenance of remission. In humans, for example, it has been reported that sulphasalazine is more effective for Hospital records of dogs in which IBD had been diagnosed at the University of Edinburgh’s Hospital for Small Animals were retrospectively reviewed. Criteria for inclusion in the study were: histopathological evidence of gastric, small intestinal or colonic inflammation on either endoscopic or surgical biopsies; clinical signs consistent with IBD; exclusion of other possible causes of symptoms, such as exocrine pancreatic insufficiency, infectious agents, endoparasites or neoplasia; and owner availability for follow-up information. The following information was accrued: signalment, clinical signs on presentation, duration of clinical signs prior to diagnosis, haematological and biochemical abnormalities, histopathological 34 M. CRAVEN EJCAP - Vol. 16 - Issue 1 - April 2006 diagnosis of disease type, site and severity, and treatment prescribed. Follow-up information was obtained from the owners using a telephone questionnaire (Fig 1). Referring veterinary surgeons were also contacted if additional information was needed. dogs was 4.3 years (mean 4.9 years, range six months to 14 years). Forty-nine dogs were male (38 entire, 11 neutered) and 31 were female (eight entire, 23 neutered). Seventy-three dogs representing 27 purebreeds were affected as well as seven dogs of mixed breed. The most commonly affected breeds were German shepherd dogs (n=18), golden retrievers (n=8), West Highland white terriers (n=6), boxers (n=6), Labradors (n=4), Border collies (n=3) and weimaraners (n=3). Disease outcome at the time of follow-up was described as either ‘remission,’ ‘intermittent signs’ or ‘uncontrolled disease’. Dogs in remission were defined as having been free of clinical signs for the preceding six months. Those with intermittent clinical signs were defined as experiencing clinical signs maximally every 14 days. Dogs with uncontrolled disease were defined as those experiencing clinical signs more frequently than every 14 days. Quality of life was defined by the owner’s perception of the animal’s general demeanour and well-being, ability and willingness to perform its usual daily activities, and level of interaction with the owner. Clinical signs and site of disease Animals were classified according to histopathology as having ‘upper’ disease (gastritis and/or enteritis, n=22), ‘lower’ disease (colitis, n=32) or ‘diffuse’ disease (upper and lower, n=26). The clinical signs according to site of disease are shown in Table 2. The median duration of clinical signs prior to diagnosis (Fig 2) was 9.5 months (mean 13.8 months, range 0.5 to 78). Laboratory findings The Kruskal-Wallis test was used to compare the disease outcome with site of disease, histopathological diagnosis, protein status and treatment. Spearman Rank Correlation was employed to compare the disease severity, the duration of clinical signs prior to diagnosis and the quality of life score with outcome. The comparisons of diet and treatment with outcome were examined with the Wilcoxon-Mann-Whitney test. Statistical significance was associated with a P value less than 0.05. Haematology was performed for 77 dogs and abnormalities (Table 3) were present in 25 dogs (32 per cent), including anaemia in nine dogs (12 per cent), leucocytosis in five dogs (6 per cent) and leucopenia in six dogs (8 per cent). Of the three dogs with eosinophilia, none had eosinophilic enteritis. RESULTS Serum biochemical abnormalities (Table 3) were observed in 67 out of 77 dogs tested (87 per cent). Hypoproteinaemia was present in 50 dogs (65 per cent) and, of these dogs, 31 (40 per cent) had a low total serum protein level and normal albumin and globulin level. Twelve animals (16 per cent) were hypoalbuminaemic (five upper, six diffuse, one lower), three (4 per Fifteen dogs (19 per cent) had platelet abnormalities. Ten dogs (13 per cent) were thrombocytopenic and thrombocytosis was present in five dogs (6 per cent). Signalment Eighty dogs, identified from hospital case records between 1995 and 2002, fulfilled the inclusion criteria. The median age of the 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Is the patient still alive? Yes If dead, what was the cause of death? How is the patient? Remission Intermittent signs Clinical signs when diagnosed: Vomiting Diarrhoea Tenesmus Mucus Frequency Haematochezia Melaena Haematemesis Weight Appetite Quality of life at the time of diagnosis? (1-10) Quality of life now? (1-10) When did the patient last show clinical signs? How frequently do clinical signs occur? When did the patient last need drug therapy? What drugs have been prescribed and what was the response? Diet at the time of diagnosis? Fig 1. Canine Inflammatory bowel disease questionnaire 35 No Uncontrolled disease Canine inflammatory bowel disease Clinical sign* Upper n=22 (per cent) Lower n=32 (per cent) Diffuse n=26 (per cent) Vomiting Diarrhoea Haematochezia Frequency† Mucus Tenesmus Melaena Haematemesis Weight loss Polyphagia Inappetence 15 (68) 13 (59) 3 (14) 1(5) 3 (14) 1 (5) 1 (5) 2 (9) 11 (50) 4 (18) 2 (9) 16 (50) 29 (91) 19 (59) 17 (53) 26 (81) 12 (38) 1 (3) 0 12 (38) 2 (6) 9 (28) 19 (73) 23 (89) 14 (54) 9 (35) 16 (62) 12 (46) 2 (77) 3 (12) 13 (50) 4 (15) 5 (19) (6/16) was 155 iu/litre (range 3 to 429). Alkaline phosphatase was elevated in 18 dogs (23 per cent); mean elevation in those not on steroids (12/18) was 57 iu/litre (range 2 to 187) and in those on steroids (6/18) was 998 iu/litre (range 54 to 3390). Hyperlipasaemia occurred in 12 dogs (16 per cent), and hyperamylasaemia occurred in 11 dogs (14 per cent). Urea was elevated in 10 dogs (13 per cent) and creatinine was elevated in 14 dogs (18 per cent). Three dogs (4 per cent) were hypocalcaemic. However, following correction for hypoalbuminaemia all were normal, except one dog in which corrected calcium was 1.86 mmol/litre (reference range 2 to 3) with unknown cause. Folate was increased in 18 dogs (mean elevation 3.9 µg/litre, range 2.0 to 25.0) and decreased in three dogs (mean reduction 2.6 µg/litre, range 1.0 to 4.7). Cobalamin was decreased in five dogs (mean reduction 92.7 ng/litre, range 76.4 to 100.0). Absolute values are not reported since the reference ranges for these parameters changed during the study period.aa *Most animals had multiple clinical signs †Increased frequency of defaecation Table 2. Clinical signs reported for 80 dogs according to site of disease Histopathology Endoscopy was performed in 77 dogs and biopsies were diagnostic of IBD in 70. Surgical biopsies were obtained in 10 dogs: four in which endoscopic biopses were normal, one with a non-diagnostic endoscopic biopsy, two in which the small intestine could not be entered endoscopically, and three with severe clinical signs. Histopathology was diagnostic of IBD in all of these dogs. Interestingly, inflammation was found to be submucosal in two dogs. cent) were hypoglobulinaemic (two diffuse, one lower) and four (5 per cent) were panhypoproteinaemic (two upper, two diffuse). Alanine aminotransferase was elevated in 16 dogs (21 per cent); mean elevation in those not receiving steroids (10/16) was 40 iu/litre (range 1 to 119 iu/litre) and in those receiving steroids Table 3. Biochemical and haematological abnormalities for 77 dogs Laboratory abnormality Number (per cent) Mean Unit Range Reference range Anaemia (PCV) Thrombocytosis Thrombocytopenia Leucocytosis Leucopenia Neutrophilia Neutropenia Eosinophilia Low total protein Hypoalbuminaemia Hypoglobulinaemia Panhypoproteinaemia Elevated urea Elevated creatinine Elevated ALT Elevated AP Hyperlipasaemia Hyperamylasaemia Hypocalcaemia 9 (12) 5 (7) 10 (13) 5 (7) 6 (8) 5 (7) 2 (3) 3 (4) 31 (40) 12 (16) 3 (4) 4 (5) 10 (13) 14 (18) 16 (21) 18 (23) 12 (16) 11 (14) 1(1) 30 750 145 20.4 5.0 17.4 3.0 1.4 55.1 19 16.2 25.4 1.3* 14.2* 83.1* 370* 385.4* 10.0* 1.86 per cent 109/litre 109/litre 109/litre 109/litre 109/litre 109/litre 109/litre g/litre g/litre g/litre g/litre mmol/litre µmol/litre Iu/litre Iu/litre iu/litre µmol/litre mmol/litre 17 to 37 576 to 942 66 to 195 17.2 to 29.0 4.4 to 5.6 12.9 to 26.0 2.8 to 3.1 1.3 to 1.5 47.7 to 57.9 7.2 to 25.7 15.6 to 16.0 19.8 to 30.2 0.1 to 4.3* 2 to 40* 1 to 429* 2 to 3390* 7 to 1915* 1.5 to 19.8* 39 to 55 200 to 500 200 to 500 6 to 15 6 to 25 3·6 to 12 3·6 to 12 0 to 1 58 to 73 26 to 35 18 to 37 58 to 73 *Mean elevation in parameter (due to changes in the laboratory reference range) PVC Packed cell volume, ALT Alanine aminotransferase, AP Alkaline phosphatase 36 2 to 3 M. CRAVEN Duration of clinical signs (months) 84 - • 72 60 - EJCAP - Vol. 16 - Issue 1 - April 2006 approaches statistical significance, in that the nonimmunosuppressed animals had a better outcome (P=0.051). • Of the 32 dogs with lower disease, 17 received immunosuppressive treatment and 15 did not. In animals with diffuse disease, 17 were immunosuppressed and five were not. No significant association between treatment and outcome was demonstrated for either of these groups (P=0.37 and P=0.12, respectively). • • 48 - • 36 - • 24 - Diet 12 0- Remission Intermittent Prescription diets were fed to 38 dogs (51 per cent), the normal diet was continued in 30 dogs (40 per cent) and the diet was not known for the remaining six dogs (8 per cent). The type of diet was not associated with outcome (P=0.64). Uncontrolled Euthanased due to IBD Fig 2. Duration of clinical signs before diagnosis of inflammatory bowel disease (IBD) Quality of life The quality of life at diagnosis and follow-up (Fig 3) was reported for 63 of the 74 dogs still alive. The score at the time of diagnosis was allocated retrospectively for some animals, and 11 of the 74 owners felt either unable to recall their dog’s quality of life at the time of diagnosis or unable to equate quality of life with a numerical score. The median quality of life score at the time of diagnosis was 3 (interquartile range 2 to 5) and at followup this had increased to 9 (interquartile range 8 to 10). The median change in quality of life score between diagnosis and follow-up was 5 (interquartile range 3 to 6.5). Only three (5 per cent) of the dogs were thought to have had no change in quality of life and none had a decrease in quality of life. The quality of life at follow-up was found to be significantly associated with outcome (P= 0.006) (Fig 4). Inflammation was described as lymphocytic in six dogs (7.5 per cent), lymphocytic-plasmacytic in 38 dogs (47.5 per cent), eosinophilic in six dogs (7.5 per cent) and non-specific (ie, a mixed inflammatory cell population) in 30 dogs (37.5 per cent). The disease was reported to be severe in 12 dogs (15 per cent), moderate in 39 dogs (49 per cent) and mild in 29 dogs (36 per cent). The severity of disease was subjectively assessed by each pathologist by consideration of the degree of inflammatory infiltrate and architectural changes within the mucosa, lamina propria, crypt epithelium and deeper tissues when visualised. In 16 out of 80 dogs (20 per cent), gastric Helicobacter was also present. Gastric inflammation was present in 14 of these dogs, but none had exclusively gastric inflammation (six upper, one lower and nine diffuse). Animals were excluded from the study if inflammation was confined to the gastric mucosa in the presence of gastric Helicobacter. Outcome At follow-up, 21 out of 80 dogs (26 per cent) were classified as being in ‘remission’. Of these dogs, 19 (90 per cent) were no longer receiving treatment and two (10 per cent) were receiving intermittent or ‘pulse’ treatment. The median duration of remission was 14 months (mean 20 months, range six to 55 months). Treatment Medications prescribed most frequently were prednisolone (n=45/74, 61 per cent) and sulphasalazine (n=26/74, 35 per cent). Azathioprine was prescribed infrequently as primary treatment (n=1, 1.4 per cent) and was more often used when other treatments had failed (n=9, 12 per cent). Metronidazole was prescribed for 14 dogs (19 per cent), tylosin for 17 dogs (23 per cent) and oxytetracycline for one (1.4 per cent). Ranitidine, omeprazole and sucralfate were the remaining drugs prescribed. Initial therapy usually consisted of more than one drug and many different combinations were given. Meaningful statistical analysis was difficult given the variety of drug combinations. Analysis was therefore confined to the effects on outcome of immunosuppressive (azathioprine 1 to 2 mg/kg/day and prednisolone 1 to 4 mg/kg/day) versus non-immunosuppressive treatment (prednisolone <1 mg/kg/day, sulphasalazine, metronidazole, tylosin, oxytetracycline, ranitidine, omeprazole and sucralfate). Forty dogs (50 per cent) were classified as having an ‘intermittent’ status, for a median duration of 17 months (mean 19 months, range seven to 64 months). Of these, 26 (65 per cent) were still receiving treatment (eight pulse, 18 continuous). The median frequency of relapse was approximately every three months, ranging from every 14 days to every five months. Three dogs (4 per cent) were classified as having ‘uncontrolled’ IBD, for a median duration of 19 months (mean 18 months, range 10 to 25 months). Ten dogs were euthanased due to refractory IBD. Prior to severe relapse and subsequent euthanasia, four had been in complete remission and off treatment for a median period of 21 months (mean 21 months, range eight to 32 months). Three had had an intermittent status for a median of 10 months prior to euthanasia (mean nine months, range six to 11 months). The remaining three dogs had failed to respond to initial treatment for a median period of three months (mean three months, range one Of the 20 dogs with upper disease, 13 received immunosuppressive treatment (three had mild disease, seven moderate and three severe) and seven did not (two had mild disease and five moderate). The association with outcome for these animals 37 Canine inflammatory bowel disease 30 - 40 - 20 - 30 - 15 - Number of dogs Number of dogs 25 - 10 501 2 3 4 5 6 7 8 9 10 20 - 10 - Quality of life Score at diagnosis Score at follow-up 00 Fig 3. Quality of life at the time of diagnosis and at follow-up 12 24 36 48 60 Length of follow-up (months) 72 84 Fig 5. Length of follow-up after diagnosis of inflammatory bowel disease 10 - DISCUSSION Quality of life score 98- The signalment, clinical signs, laboratory findings and type of disease reported in this paper are similar to previous studies (Jacobs and others 1990, Jergens and others 1992). Comparison of signalment with the hospital population over the same time period was not possible due to its system of record keeping. 76543- Ten animals (12.5 per cent) were thrombocytopenic and it has been postulated that this may be causally associated with IBD in both humans and dogs (Ridgway and others 2001). The incidence of thrombocytopenic dogs in the previous study was lower, at 2.5 per cent of the authors’ population, and an immunological basis was hypothesised. It is reported in humans that the thrombocytopenia may or may not resolve with treatment of IBD, and unfortunately follow-up platelet counts for dogs are rarely available. Thrombocytosis was present in five dogs (7 per cent) and, although it is a common human extraintestinal manifestation of IBD, a causal association has not been reported in dogs. In human studies, the thrombocytosis is proportional to the activity of the disease, and is related to a reduced half-life and increased platelet turnover (Talstad and others 1973). Subjectively, there did not appear to be any association with severity of disease in the present study. These findings suggest that abnormalities in platelet number may have a causal association with canine IBD, and further investigation is needed to discover the pathophysiological mechanisms involved. 21Remission Intermittent signs Uncontrolled disease Fig 4. Quality of life and outcome to five months). Interestingly, seven of these animals were hypoalbuminaemic at the time of diagnosis and two had achieved clinical remission for 18 and eight months prior to severe relapse and subsequent euthanasia. The remaining six dogs had been euthanased for reasons unrelated to IBD or had died of an unrelated cause. These six dogs were excluded from further statistical analysis as the status of their IBD was unknown. The median duration of clinical signs prior to diagnosis was 9.5 months (mean 13.8 months, range two weeks to 78 months) and this was not significantly associated with outcome (P=0.85) (Fig 2). The median length of follow-up after diagnosis of IBD (Fig 5) was 17 months (range one to 64 months) and this was found to have no association with outcome (P=0.18). Hypoalbuminaemia was strongly associated with a poor outcome (P=0.0007). The pathophysiology of hypoproteinaemia may involve reduced appetite, malabsorption due to a reduction in intestinal surface area, such as with villus atrophy or fibrosis, haemorrhage or exudation of protein into the gastrointestinal tract, and increased intestinal permeability. Hypoalbuminaemia may be expected to occur with disease of greater severity and indeed this has been reported in human IBD (Griffiths and others 1986, Cabral and others 2001). Surprisingly, the histopathological severity of disease in four out of seven severely hypoalbuminaemic animals (albumin <15 g/litre) was graded No association was found between outcome and the site (P=0.75), type (P=0.44) or severity of disease (P=0.75) (Table 4). Hypoalbuminaemia, however, was strongly associated with a negative outcome (P=0.0007), whereas low total protein and normal protein were not associated with outcome. 38 M. CRAVEN EJCAP - Vol. 16 - Issue 1 - April 2006 Site of disease Remission Intermittent signs Uncontrolled disease Euthanased due to IBD Upper (n=20) (gastritis and/or enteritis) Lower (n=32) (colitis) Diffuse (n=22) (upper and lower) 9 (45) 6 (30) 0 (0) 5 (25) 6 (19) 23 (72) 2 (6) 1 (3) 6 (27) 11 (50) 1 (5) 4 (18) IBD Inflammatory bowel disease Table 4. Number (per cent) of dogs with each outcome by site of disease as mild or moderate. The authors found no association between the site, type and severity of disease and outcome. These parameters, therefore, appear to be of little prognostic value, and in particular the association of a worse outcome with eosinophilic disease previously mentioned is not supported. may have had subclinical disease. It is interesting to note, however, that the vast majority of animals in remission (90 per cent) did not receive medical therapy, in contrast to the intermittent group in which 65 per cent were receiving medical treatment. The variable length of follow-up and the retrospective nature of this study did not permit accurate assessment of relapse rates. In human IBD, one-year relapse rates are generally reported as being around 50 per cent (Kornbluth and others 1995, Elton and Hanauer 1996), and a longer duration of remission has been associated with a lower relapse rate (Ardizzone and others 1999). It is alarming to note that four of the animals that were euthanased due to IBD had achieved remission times ranging from between eight and 32 months in length, prior to severe relapse and euthanasia. The remission rate reported here was 26 per cent, and this is considerably lower than for human IBD, where reported first remission rates are 75 to 85 per cent (Brignola and others 1992, Kornbluth and others 1995, Moum 2000). However, the criteria used to define remission are incomparable. Activity indices, specifically the Crohn’s Disease Activity Index (Best and others 1976) and the Harvey Bradshaw Index (Harvey and Bradshaw 1980) have been widely employed in human clinical trials, and scores below a certain threshold are indicative of clinical remission. Faecal calprotectin, microalbuminuria, intestinal permeability measurements, serum C-reactive protein and gut lavage inflammatory markers have also been correlated with disease activity in humans (Arnott and others 2002). The association between human IBD, in particular ulcerative colitis, and colorectal cancer is well recognised (Ribeiro and others 1996, van Hogezand and others 2002). An increased incidence of neoplastic disease was not discovered among the animals in the present study; however, in the 10 animals that were euthanased due to refractory IBD, postmortem examination was not performed and thus neoplasia cannot be excluded. Currently, there are no recognised criteria for characterisation of the clinical status of canine IBD. The criterion applied in this study were based on the frequency of recurrence of clinical signs, and it is accepted that the criteria for remission (free of clinical signs for six months) may be inappropriate, thus resulting in an artificially lower remission rate. The reason for the somewhat strict remission criterion is attributable to the retrospective nature of the study. Very few owners kept records of their pet’s health, and the assumption was that memory recall would be more likely to lead to underestimation of symptomatic episodes as opposed to overestimation. The six month period was therefore applied in the hope that this would identify a group of dogs in which clinical signs had been quiescent for reasonably long periods of time. Development of canine activity indices (Jergens 2002) and evaluation of potential markers of disease, such as faecal alpha-1 protease inhibitor and microalbuminuria, may in the future enable more accurate assessment of clinical status. Owner-evaluated quality of life at follow-up was significantly associated with outcome (P=0.006). Given the subjectivity of this parameter, such a strong association was unexpected and implies that owner perceptions are a valid aspect of disease monitoring. The present study could have been improved had the histopathology been interpreted by one pathologist using predefined criteria. Significant interobserver variation in histopathological evaluation of tissues has been reported (Willard and others 2002). However, currently no widely accepted histopathological grading schemes for the diagnosis of canine IBD exist. Little useful information has been gleaned from this study regarding the treatment of canine IBD, and this is perhaps not surprising with retrospective evaluation of a disease with such varied treatment options. Well-designed prospective clinical trials will better serve this purpose, and are long overdue in this field. Widespread standardisation of clinical and pathological The importance of histological remission as well as clinical remission is recognised, and it is well accepted in human IBD that these two descriptors may not be coincident (Arnott and others 2002). Repeat biopsy was rarely performed in this study, hence it is possible that some of the animals classified as being in remission 39 Canine inflammatory bowel disease – implications for therapy. Journal of Feline Medicine and Surgery 4, 179-182 KORNBLUT (A.), MARION (J.F.), SALOMON (P.), JANOWITZ (H.D.) (1995) - How effective is current medical therapy for severe ulcerative and Crohn’s colitis? 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Surgery Clinics of North America 81, 71-101 STOKES (J.E.), KRUGER (J.M.), MULLANEY (T.), HOLAN (K.), SCHALL (W.J.) (2001) - Histiocytic ulcerative colitis in three non-boxer dogs. Journal of the American Animal Hospital Association 37, 461-465 TALSTAD (I.), ROOTWELT (K.), GJONE (E.) (1973) Thrombocytosis in ulcerative colitis and Crohn’s disease. Scandinavian Journal of Gastroenterology 8, 135 THOMPSON (A.B.R.) (1991) - New developments in the use of 5aminosalicylic acid in patients with inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 5, 449 WILLARD (M.D.), JERGENS (A.E.), DUNCAN (R.B.), LEIB (M.S.), MCCRACKEN (M.D.), DENOVO (R.C.), HELMAN (R.G.), SLATER (M.R.), HARBISON (J.L.) (2002) - Interobserver variation among histopathologic evaluations of intestinal tissues from dogs and cats. Journal of the American Veterinary Medical Association 220, 1177-1182 WITTE (J.), SHIVANANDA (S.), LENNARD-JONES (J.E.), BELTRAMI (M.), POLITI (P.), BONANOMI (A.), TSIANO (E.V.), MOUZAS (I.), SCHULZ (T.B.), MONTEIRO (E.), CLOFENT (J.), ODES (S.), LIMONARD (C.B.), STOCKBRUGGER (R.W.), RUSSEL (M.G.) (2000) - Disease outcome in inflammatory bowel disease: mortality, morbidity, and therapaeutic management of a 796person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Scandinavian Journal of Gastroenterology 12, 1272- 1277 WRIGHT (J.P.) (1992) - Factors influencing first relapse in patients with Crohn’s disease. Journal of Clinical Gastroenterology 15, 12-16 VAN HOGEZAND (R.A.), EICHHORN (R.F.), CHOUDRY (A.), VEENENDAAL (R.A), LAMERS (C.B.) (2002) - Malignancies in inflammatory bowel disease: fact or fiction? Scandinavian Journal of Gastroenterology 236, 48-53 grading systems and definition of criteria denoting clinical status will be of paramount importance for such therapeutic trials to be of comparative value.aa ACKNOWLEDGEMENTS The authors would like to thank Robert Lee, of the Medical Statistics Unit, University of Edinburgh, for performing the statistical analysis. REFERENCES ARDIZZONE (S.), PETRILLO (M.), IMBESI (V.), CERUTTI, (R.), BOLLANI (S.), PORRO (B.G.) (1999) - Is maintenance therapy always necessary for patients with ulcerative colitis in remission? Alimentary Pharmacology and Therapeutics 13, 373-379 ARDIZZONE (S.), PORRO (G.B.) (2002) - Inflammatory bowel disease: new insights into pathogenesis and treatment. Journal of Internal Medicine 252, 475-496 ARNOTT (I.D.R.), WATTS (D.), GHOSH (S.) (2002) Review article: is clinical remission the optimum therapeutic goal in the treatment of Crohn’s disease? Alimentary Pharmacology and Therapeutics 16, 857-867 BEST (W.R.), BECKTEL (J.M.), SINGLETON (J.W.), KERN (F.) JR. (1976) - Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 70, 439-444 BRIGNOLA (C.), DE SIMONE (G.), IANNONE (P.), BELLOLI (C.), EVANGELISTI (A.), CAMPIERI (M.), BELLUZZI (A.), GIONCHETTI (P.), TAMPIERI (M.), BERTINELLI (E). (1992) Influence of steroid treatment’s duration in patients with active Crohn’s disease. Agents Actions C90-92 CABRAL (V.L.), DE CARVALHO (L.), MISZPUTEN (S.J.) (2001) Importance of serum albumin values in nutritional assessment and inflammatory activity in patients with Crohn’s disease. Arquivos de Gastroenterologia 38, 104-108 CHURCHER (R.K.), WATSON (A.D.) (1997) - Canine histiocytic ulcerative colitis. Australian Veterinary Journal 75, 710-713 ELTON (E.), HANAUER (S.B.) (1996) - Review article: the medical management of Crohn’s disease. Alimentary Pharmacology and Therapeutics 10, 1-22 GERMAN (A.J.) HALL, (E.J.), DAY (M.J.) (2003) - Chronic intestinal inflammation and intestinal disease in dogs. Journal of Veterinary Internal Medicine 17, 8-20 GRIFFITHS (A.M.), DROBNIES (A.), SOLDIN (S.J.), HAMILTON (J.R.) (1986) - Enteric protein loss measured by fecal alpha 1antitrypsin clearance in the assessment of Crohn’s disease activity: a study of children and adolescents. Journal of Pediatric Gastroenterology 5, 907-911 HALL (E.), SIMPSON (K.) (2000) - Diseases of the small intestinal disease. In: Textbook of Veterinary Internal Medicine. Eds S. J. Ettinger and E. C. Feldman. W. B. Saunders, Philadelphia. pp 1137-1182 HENDRICKSON (B.A.), GOKHAL (R.), CHO (J.H.) (2002) - Clinical aspects and pathophysiology of inflammatory bowel disease. Clinical Microbiology Reviews 15, 79-74 HARVEY (R.F.), BRADSHAW (J.M.) (1980) - A simple index of Crohn’s-disease activity. Lancet 1, 514 JACOBS (G.), COLLINS-KELLY (L.), LAPPIN (M.), TYLER (D.) (1990) - Lymphocytic-plasmacytic enteritis in 24 dogs. Journal of Veterinary Internal Medicine 4, 45-53 JERGENS (A.E.), MOORE (F.M. HAYNES (J.S.), MILES, (K.G.) (1992) - Idiopathic inflammatory bowel disease in dogs and cats: 84 cases (1987-1990) Journal of the American Veterinary Medical Association 201, 1603-1608 JERGENS (A.E.) (2002) - Understanding gastrointestinal inflammation More about FECAVA and EJCAP visit: www.fevava.org 40 REPRINT PAPER (F) T ranspelvic urethrostomy (TPU) in the cat: a new technique. Prospective survey: 19 cases A. Bernardé(1), E. Viguier(2) S U M M A R Y The purpose of this prospective study was to investigate the feasibility and long-term outcome of a modified subpubic urethrostomy in the cat, termed transpelvic urethrostomy (TPU). Nineteen male cats with unrelievable obstructive lower urinary tract disease (LUTD) were selected for TPU. In each case, the stoma was made from the pelvic urethra, exposed ventrally after an ischial ostectomy. There were no intraoperative complications or accidents. The pelvic urethra and bulbourethral glands were easily recognized and a patent urethral stoma, at least 2 mm in diameter, was created in all cases. There was no evidence of symptomatic urethral stricture at follow-up examinations (mean 19 months). Only 1 cat had transient postoperative urinary incontinence that resolved within 4 weeks. Three cats showed one or several episodes of LUTD after the 2 months re-examination, that were responsive to medical therapy. TPU is a successful procedure of urinary diversion in the cat with few and minor complications. This technique may be considered at least as a salvage procedure in cases of perineal urethrostomy failure (an alternative to prepubic and subpubic techniques) and possibly as a primary urinary diversion method (an alternative to perineal urethrostomy) for obstructive LUTD. KEY WORDS: Urethrostomy – Transpelvic – Cat - LUTD INTRODUCTION This paper was originally published in : Prat Méd Chir Anim Comp* (2003) 38:p.437-446 Feline urologic syndrome (FUS) is common in cats. Lower urinary tract disease (LUTD) or interstitial cystitis are acceptable terms also used to name this idiopathic inflammatory process of the feline lower urinary tract, that sometimes results in partial or complete urethral obstruction in male cats [1-4]. Obstructions affecting the penile urethra are treated by perineal urethrostomy (PU) if appropriate nonsurgical treatments (urethral catheterisation, urethral irrigations, cystostomy tubing) have failed to restore the urethral patency [4-6]. Some proximal urethral obstructions may not be amenable to such management. In these cases, more proximal urinary diversions, such as prepubic (i.e. antepubic) urethrostomy (PPU) or subpubic urethrostomy (SPU) are indicated. These techniques have also been proposed as primary treatments of penile urethral obstructions, or as salvage procedures in case of PU failure [7-10]. PU, PPU and SPU techniques in cats have been extensively described previously [5,7-14]. Potential complications are associated with these techniques. One of the most serious complication is stricture formation, mostly associated with PU. It is well recognized now that this complication is primarily due to technical errors, making the stoma too small into the proximal penile urethra (less than 1 mm in diameter) instead of the larger pelvic urethra(2 to 2.4 mm) situated below the bulbourethral (or (1) Clinique Vétérinaire des Quais, 31 quai Ulysse Besnard, F- 41000 Blois. E-Mail : [email protected] (2) Service de Pathologie Chirurgicale des Carnivores Domestiques, Ecole Nationale Vétérinaire de Lyon, BP 83, F- 69280 Marcy-L’Etoile. * Presented by AFVAC (France) 41 Transpelvic urethrostomy (TPU) in the cat bulboerectil) glands. [11-15] Postoperative subcutaneous urine leakage and subsequent granulation tissue formation may also induce a late stoma stenosis after PU and PPU. Urinary and fecal incontinence may occur if the pelvic nerves are damaged during the dissection around the pelvic urethra. Rectal prolapse has been reported following PU in cats [14-18]. PU, and more often PPU, are associated with a high prevalence of urinary tract infection (UTI) postoperatively due to the underlying urethropathy and probably also to anatomic alterations of the urethral meatus (PU) and muscles (PPU) compromising intrinsic defence mechanisms10, [14-18]. Urinary incontinence and UTI are major complications after PPU. [7,8,10] Data are lacking to describe the potential complications of the SPU technique, as it was reported in one case only. [9] SPU was used successfully as a salvage method after a failed PU and as an alternative to PPU. The author chose an anatomical urethral diversion site situated between a PU site and a PPU site. By creating the stoma effectively from the pelvic urethra, he minimised the risk of stricture associated with PU. By creating it far enough from the vesico-urethral junction of the preprostatic urethra (considered as the internal urethral sphincter), he minimised the risk of UTI and incontinence commonly associated with PPU. mg/kg/24h or cefalexin (Rilexine; Virbac, France) at 20 mg/kg/12h. Anaesthesia was induced with either an intramuscular injection of a combination of medetomidine (Domitor; Pfizer) at 4 μg/kg and ketamine (Imalgène; Merial, France) at 3-5 mg/kg, or with ketamine intravenously following subcutaneous premedication with morphine sulfate (Morphine Lavoisier; Laboratoires Chaix et Du Marais, France) at 0.02 mg/kg and acepromazine (Calmivet, Vétoquinol) at 0.1 mg/kg. Anaesthesia was maintained using isoflurane in oxygen after tracheal intubation. All cats were prepared for aseptic perineal and ventral surgery in a routine manner. They were positioned in dorsal recumbency, with the feet secured to the surgical table in a cranial position (Fig. 1). Surgical technique The surgical procedure, described below, is composed of 6 steps, numbered from 1 to 6. The first step is optional: it was used systematically for the first 13 cases of the series and abandoned later. 1. Cystotomy and placement of a urethral catheter from the urinary bladder to the urethral obstruction site. A ventral midline coeliotomy was carried out in order to expose the bladder 1.5 to 2 cm cranial to the cranial pubic margin. The ventral bladder wall was secured to the skin with 4 orthogonal sutures, and a ventral cystotomy, 4 to 6 mm long, was performed. The bladder contents were aspirated and the bladder cavity flushed with a sterile saline solution. A 6 French (2 mm) urinary catheter (for dogs) was inserted into the bladder and the proximal urethra up to the obstruction site, in order to allow later identification of the pelvic urethra. While maintained in this position, the catheter was secured to the bladder wall with a temporary purse string suture in order to avoid any urine leakage into the abdominal cavity. The purpose of this study was to document the feasibility and the long term outcome of a modified subpubic technique for urethral diversion in male cats, termed transpelvic urethrostomy (TPU), performed as a primary or secondary (salvage) technique for obstructive LUTD. MATERIALS AND METHODS All cats undergoing TPU between January 1997 and April 2002 were considered for this study. All of them were client-owned cats, presented for unrelievable obstructive LUTD, whether this event was a first occurrence, a recurrence, or the result of a failed PU. The minimum criteria for inclusion were owner approval and a minimum follow-up period of 6 months. Cats with urethropathy suspected to be of a different origin than a LUTD (neoplastic or traumatic) and cats with a concurrent disease were excluded from the study. In all cases, a biochemical blood analysis was done at admission, including at least measurements of uremia, creatinemia, proteinemia, glycemia, natremia, chloremia, kalemia, and base excess. Some urine was collected aseptically via cystocentesis and submitted for urinalysis and microscopic examination. Urine culture was requested in cases of leucocyturia, nitrite accumulation, or microscopic evidence of bacteriuria. 2. Ventral penis and subpubic adductor muscles exposure. An elleptical skin incision was made to excise the scrotum and prepuce as is done routinely for a perineal urethrostomy. This incision was extended cranially up to the cranial margin of the pubis. In entire males, the testicles were then exposed and castration was performed. The penis, being extended caudally, was undermined ventrally. After removal of some fat tissue, the caudal and ventral aspects of the pubis were exposed. The Bulbo-urethral glands, ischiocavernosus and ischiourethralis muscles were identified and left intact. Fibres from the adductor muscles, gracilis and external obturator were easily recognized, forming large V opening caudally (Fig. 2) . The caudal pubic margin was palpated at the caudal aspect of these muscles. Their median attachment corresponding to the ventral aspect of the ischio-pubic symphysis was also identified (Fig. 2). A temporary diversion technique was carried out initially, by a urethral catheterisation or a cystostomy tube technique. [19] The urethral obstruction was considered unrelievable when the obstruction recurred within 48 hours after urethral catheter removal, or when the urethral obstruction persisted despite a cystotomy tube maintained for 3 to 5 days. In such cases, the cats were considered for surgical management. 3. Ventral exposure of the ischio-pubic symphysis, ischial ostectomy and pelvic urethra exposure. Bilateral lateral muscle elevations were made in order to expose an area of the ventral aspect of the publis approximately 1.21.5 cm wide, and 1.4-1.6 cm long. Bone forceps were introduced around the pubis in a caudo-cranial direction and a progressive Surgical preparation All cats received perioperative intravenous antibiotic therapy, with either marbofloxacin (Marbocyl; Vétoquinol, France) at 2 42 A. BERNARDE, E. VIGUIER EJCAP - Vol. 16 - Issue 1 - April 2006 Fig. 1 The cat is positioned in dorsal recumbency, with the feet secured to the surgical table in a cranial position. This position helps later exposure of the ischio-pubic symphysis. Fig. 4 Pelvic ostectomy has been achieved. Exposure of the pelvic urethra. Fig. 2 Ventral exposure of the penis and pelvis. The penis (on the right) enters cranially under the ischio-pubic symphysis (short white arrow) whose caudal margin is the curved dotted line. Adductor muscles are easily identified by their parallel fibres, forming a large V opening caudally. Ischiourethralis and ischio-cavernosus muscles insertions, and bulbo-urethral glands are masked by fat at the ischioperineal junction (long white arrow). Fig. 5 Atraumatic manipulation of the urethral wall with DeBakey forceps after urethrotomy. Fig. 3 Ischial ostectomy with bone rongeurs after bilateral elevation of the adductor muscles from the ischio-pubic symphysis. Fig. 6 Urethro-cutaneous anastomosis completed. 43 Transpelvic urethrostomy (TPU) in the cat Fig. 7 Urethrostomy diameter is tested. The blunt tip of a 6-Fr catheter is introduced approximately 1 cm into the stoma without difficulty. Fig. 8 The meatus is protected with a copious amount of Vaselinecontaining ointment (Fucidine cream ND, Léo). Fig. 9 Positive contrast radiography of the urethra postoperatively (case number 3). The arrow points to the urethrostomy site. Caudally, the ischio-pubic table is lacking. Fig. 10 Peristomal urine staining in a Persian cat (case number 5). Despite hair being moist and discoloured, there is no dermatitis. ostectomy was performed, producing an ostectomy area approximately 10 mm wide and 12 mm long. Care was taken to involve no soft tissue within the excision (Fig. 3). After this ostectomy the pelvic urethra was visualised or, where a catheter was used, palpated with the catheter inside (Fig. 4). 5. Urethrostomy. Care was taken to manipulate the urethral wall with non traumatic De Bakey forceps. The urethral wall was everted bilaterally (Fig. 5). Suturing of the urethral mucosa to the skin margins was accomplished without tension via a simple interrupted pattern of 4-0 or 3-0 monofilament polypropylene or polyamide sutures, beginning at the 4 cardinal limits of the urethrotomy. In some overweight cats, some fat tissue surrounding the stoma site was excised to reduce tension on the sutures. The part of the penis distal to the bulbo-urethral glands was amputated, and additional simple interrupted sutures were placed to achieve the urethro-cutaneous anastomosis (Fig.6). 4. Urethrotomy. When present, the catheter facilitated identification of the urethra. Otherwise, the urethral lumen was identified after transection of the penis at the level of the bulbourethral glands and a 6 Fr catheter was introduced into the urethra in a cranial direction. A ventral longitudinal urethral incision was made over the catheter with a number 15 scalpel blade or with iris scissors, from the level of the bulbo-urethral glands to a point situated 2 to 3 mm from the cranial margin of the ostectomy. The urethrotomy was approximately 10 to 12 mm long on the ventral aspect of the urethra. 6. Skin closure. Additional skin sutures were used to close the wound cranial and caudal to the stoma site. The catheter was removed from the bladder, and introduced into the urethrostomy to test its diameter (Fig. 7). Bladder wall and coeliotomy wound were 44 A. BERNARDE, E. VIGUIER EJCAP - Vol. 16 - Issue 1 - April 2006 closed routinely. The urethrostomy site was protected with a vaseline containing ointment (Fucidine Leo; Laboratoires Leo, France) (Fig. 8). Urethral catheterisation had been performed as initial management of the obstructive disease in 8 cases only, for 2 to 4 days. For the other 6 cases, urethral catheterisation had been impossible and a cystostomy tube had been placed for 4 to 7 days. For each of these 14 cats, the urethral obstruction had been considered non-relievable as the urethral patency did not recover after placement of the catheter or before the tube removal. In the remaining 5 cats (3 with a stricture following a failed PU, 2 with LUTD recurrence) the TPU was conducted once the bladder was evacuated by cystocentesis. Post operative care An Elizabethan collar was placed on each cat immediately after recovery from anesthesia to prevent self-mutilation of the surgical site. Positive contrast radiography of the urethra was performed immediately post surgery in 3 of the first 10 surgical cases (Fig. 9). Surgical Technique All cats received postoperative antibiotic therapy for 5 to 8 days with either marbofloxacine (Marbocyl; Vetoquinol S.A., France) at 2 mg/kg intravenously or orally once a day, or cefalexine (Rilexine; Virbac S.A., France) at 20 mg/kg intravenously or orally every 12 hours. They also received analgesic drugs with either morphine (Morphine Chlorhydrate Lavoisier; Laboratoires Chaix et Du Marais, France) at 0.02 to 0.04 mg/kg subcutaneously every 4 to 6 hours for 24 to 30 hours, or meloxicam (Metacam; Boehringer Ingelheim Vetmedica GmbH, Germany) at 0.15 mg/kg subcutaneously once a day for 1 to 3 days, or a combination of the two. All cats were monitored postoperatively for urine output. Cats were hospitalised until voluntary urination had been present for 48 hours. The vaseline containing ointment was applied to the urethrostomy site 3 to 4 times per day until suture removal at 10 to 12 days postoperatively. Cats were scheduled for re-examination at 2 weeks, 4 weeks, 3 months and 6 months after surgery. On each occasion, the stoma diameter was tested as previously described. Additional follow-up data were collected by phone from the owners and referring veterinarians. Recommendations for dietary management of LUTD were made for all cats that had suffered from this syndrome before presentation. In all cases, all consecutive steps times of the procedure, (ie. ventral dissection of the penis, elevation of the adductor muscles and public ostectomy) were achieved without complication. The first step of the procedure, i.e. insertion of a bladder catheter, was done in the first 13 cases only. The pelvic urethra was easily palpated and identified and the urethrotomy was carried out at a site such that its proximal opening was situated 15 to 18 mm below the bulbo-urethral glands. Creation of a definitive “transpelvic” stoma without undue tension on the urethra or skin was possible in all cases. In 3 cases, excessive subcutaneous fat tissue had to be removed before placing the sutures. Once the stoma was created, it was possible to introduce a 6 French catheter in all cases, indicating that the diameter of the stoma was at least 2 mm. Post-operative findings All cats tolerated the procedure well and passed urine voluntarily within 12 hours of surgery. Urinary retention or dysuria were not seen in the postoperative period. Incontinence was seen in 1 case. Premature suture loosening was seen in 1 case. All cats, except 2, were discharged between 2 and 4 days postoperatively. Only 2 cats (15%) received some form of systemic medication beyond the first 2 weeks postoperatively, which included antibiotic (1 cat with premature suture loosening), and corticosteroid (1 cat with urinary incontinence). The case with suture loosening had dislodged its Elizabethan collar prematurely. After replacement of the collar, the surgical site was cleaned twice a day with a sterile isotonic saline solution. Protection of the stoma site with vaseline ointment was continued until the wound healed by secondary intentiion after 17 days. The case with urinary incontinence was managed with prednisolone (Microsolone; Merial, France) given orally at 0.5 mg/kg twice a day from the 10th to the 15th days, and at half this dosage from the 16th to 20th days postoperatively. The urinary incontinence was resolved at day 20. RESULTS Signalment Nineteen male cats were considered for inclusion in the study. All but one were neutered males. The mean age was 6 years (range, 2 to 9 yr). Their mean body weight was 5.5 kg (3.2 to 7.5 kg). Two-thirds (13 out of 19) were considered overweight. The breeds represented were mixed breed domestic European (n=13), Persian (n=3), Siamese (n=2) and Main Coon (n=1). None of the 19 cats were uremic or hyperkalemic at the time of presentation. There was no bacterial growth in 4 out of 6 cases where urine culture was performed. Crystalluria was evidenced in 13 cases, with predominantly calcium oxalates (n=6), struvites (n=4), combination of both (n=2), and combination of struvites and bilirubin (n=1). Follow-up All cats were re-examined at 2 weeks for suture removal and at approximately 4 weeks after the surgery with particular attention paid to the urethral meatus (Fig. 10). All except one cat had a patent urethral stoma with no evidence of stricture, as demonstrated by the easy introduction of a sterile 6 French catheter into the stoma site. In the case, that had had premature suture loosening 3 weeks earlier, the introduction of such a large catheter was not possible, proving the stoma had strictured. However, the cat was not symptomatic, and the owner of that Indications for surgery Indications for TPU were: non relievable urethral obstruction secondary to a first episode of LUTD (n=4); secondary to recurrent episodes of LUTD (n=12); and stricture of the stoma site after a previous failed PU (n=3). 45 Transpelvic urethrostomy (TPU) in the cat Cas n° Age (yr) Sex Breed Indication Follow-up (months) 1 2 3 4.5 7 6 NM NM NM European European European OLUTD(2) OLUTD(3) OLUTD(2) 48 35 28 4 2 NM European OLUTD(1) 25 5 6.5 NM Persian OLUTD(2) 23.5 6 7 M European Failed PU (stricture) 22.5 7 8 NM Persian OLUTD(1) 20 8 9 4.5 5.5 NM NM Siamese European OLUTD(2) OLUTD(2) 20 18 10 11 12 13 6 7.5 4 9 NM NM NM NM European European Siamese European 17 16.5 16 13 14 15 16 17 5.5 4 8 3.5 NM NM NM NM European Main Coon Persian European OLUTD(1) OLUTD(2) OLUTD(2) Failed PU (stricture) OLUTD(2) OLUTD(3) OLUTD(1) Failed PU (stricture) OLUTD(2) LUTD(3) Early complication (<2 months) Idiopathic LUTD (4) at 7,10,14,17 mths LUTD(1) Struvite crystalluria at 17 mths Permanent peristomal urine staining Suture dehiscence at day 2 secondary intention. healing achieved at day 17 Intermittent urine staining on the leg Urinary incontinence [resolved by day 20] LUTD(1) UTI at 5mths 12.5 11 11 8 18 7.5 NM European 8 19 7 NM European 7 TOTAL 100% Table 1. TPU in 19 cats: Signalment, Indications, Complications. OLUTD (n) : Obstructive LUTD, (n) points out the number of episodes. cat did not mention any dysuria or stranguria. No other complication was seen at that time. Late complication (<2 months) Intermittent urine staining on the leg 10.5% 31.6% meatus with no evidence of stricture in all cats. Urine staining (peristomal and permanent for one cat, on the medial aspect of the feet and intermittent for two others) was unchanged. Three cats showed late clinical signs of LUTD, manifested by episodes of hematuria and dysuria, while stoma diameter was unchanged. Two of them had one single episode of LUTD at 5 months for one cat and at 17 months for the other. Urine sediments showed elevated leucocyte counts in one urine specimen collected by cystocentesis from the first cat. Bacteria were observed microscopically in this sample. Bacterial culture was positive, and bacteria were not sensitive to the antibiotic used postoperatively. Bacterial urinary infection was not demonstrated in the other cat, but struvite crystalluria was present. The owner had not continued the dietary treatment, returning to a non-specific commercial food. These two cats responded well to antibiotic therapy and dietary management, respectively, and no other episodes of hematuria and dysuria were noticed during the follow-up period ranging from 8 to 15 months. The third cat had several recurrent episodes of hematuria-dysuria at 7, 10, 14 and 17 months, thus approximately once every three months after the 7th month. Despite two urine cultures at 7 and 14 months, All cats were re-examined approximately 3 months after the surgery. At that time, the hair around the stoma site had returned to its original length. All urethrostomies were patent, with no difference in diameter from the previous follow-up control. One continent cat had chronic urine staining of the ventral abdomen due to retention of urine in the hair surrounding the stoma site (Fig. 11). Two cats had intermittent urine staining on one of their feet. According to the owners of these cats, it was intermittent, depending on their position during micturition. All other cats seemed to have adopted an altered position during micturition, and these problems were not noticed. No other complication were seen at that time. All cats were re-examined 3 to 5 months later (scheduled 6th month follow-up examination), and later additional follow-up data were collected by phone from the owners and referring veterinarians for all cats except one which died as a result of a road traffic accident. Urine passed freely through the urethral 46 A. BERNARDE, E. VIGUIER EJCAP - Vol. 16 - Issue 1 - April 2006 cats are well documented. Transient, short-term complications are relatively common and usually transient. They include dysuria, pollakiuria, hematuria, hemorrhage from erectile tissue and partial or complete dehiscence of the urethral flap [2,812,14-18] Dehiscence may result from excessive suture tension (inherent to the surgical technique), or accidental self-mutilation (non-inherent to the technique) because of an inadequate or badly-attached Elizabethan collar. Only one cat had partial suture dehiscence, because of premature loosening of the cervical collar and excessive leaking of the meatus. This accident had no severe consequence as the urinary meatus healed well by secondary intention healing. After this accident, we revised our method of fixation of the Elizabethan collar, using a hand-made harness rather than a simple collar. There was no futher occurence of dehiscence. The lack of spontaneous dehiscence proves that excessive suture tension is not a particular problem with TPU. a bacterial infection was not evidenced. A moderate struvite crystalluria was seen despite strict adherance to dietary management. Each episode responded well to an antispasmodic therapy (Spasmoglucinol, Vétoquinol, France). An anxiolytic drug (Clomicalm, Novartis,) was also given daily for one month and every two days subsequently, and no recurrence was seen up to 28 months postoperatively. The mean overall follow-up of the nineteen cases was 19 months. DISCUSSION Urethrostomy is indicated for the permanent relief of urethral obstruction in male cats. Obvious but uncommon indications are irreversible trauma and neoplasia. [2,14] Obstructive LUTD secondary to matrix crystalline plugs or uroliths that cannot be managed medically are indications for urethrostomy too, to circumvent the life-threatening consequences of urethral obstruction [4,13,14,18]. Long-term complications have also been reported, including four main types: stricture of the stoma site, urinary incontinence, urinary tract infection, and chronic urine-scald dermatitis [8-18,20,21]. The complication rates reported depend on the technique used: PU is associated mostly with the risks of stricture and infection whereas PPU is associated with all the above risks. [7,8-17,19]. Other occasional long-term complications, such as undetected presurgical or intrasurgical rupture of the urethra (mostly following catheterization) with later extravasation of urine into the perineal tissue, rectal prolapse as well as faecal incontinence, rectourethral fistula and perineal hernia were also reported after PU [7,14,17]. Stricture or stenosis of the urinary meatus is a common concern after PU. In one study, urethral stricture was reported in 37 of 204 cats after PU. All resulted from incomplete mobilisation and dissection of the penis and its pelvic attachments with failure to extend properly the urethral incision to the level of the pelvic urethra [13]. In another study, of 29 cats referred to a teaching hospital for complications after PU, 22 had urethral stricture, although the sites of stricture were not specified [15]. Taking into account past errors, improvements to the original PU of Wilson and Harisson [5] were proposed. More recent studies of PU with proper urethral opening 1 cm below the bulbo-urethral glands reported stricture infrequently [13,15,18]. This risk is minimal with SPU and PPU as these techniques involve portions of the urethra respectively pubic and abdominal, that are 3 to 4 times wider than the perineal portion [15]. It was therefore expected that the TPU technique reported here would avoid this complication, as the proximal margin of the urethrostomy was 15 to 18 mm below the bulbo-urethral glands. TPU did not result in any symptomatic meatus stricture. In all cases but one, the diameter of the urinary meatus remained large enough to accept easily the entrance of a 6 Fr. catheter at long-term re-examinations. Indications for the procedure used in this study were unrelievable obstruction of the perineal urethra secondary to LUTD (n=16) or stricture following a previous perineal urethrostomy (n=3). Except in 5 cases (3 post PU meatus stenosis, 2 recurrent spontaneous obstructive LUTD) , all had preliminary ineffective attempts to reverse the urethral obstruction by non surgical means, either by transurethral catheterisation and reverse flushing (n=8) or by temporary cystostomy (n=6). Even if these methods should be preferred to surgical procedures [4,14,19] there is no data in the literature allowing an assessment of their efficacy. During the inclusion period of this survey (from January 1997 to April 2002), 13 other cats that were presented with a urethral obstruction were managed successfully by either urethral catheterisation (n=13) or cystostomy (n=2) and were not treated surgically. All cats selected for TPU were male. All but one had been neutered with a mean of 3 years between neutering and first episode of LUTD. No breed predilection was noticed. European mixed breed cats were over-represented, with a similar ratio to the overall population of cats presented to our hospitals. Obesity seemed to represent a predisposing factor for obstructive LUTD as two-thirds of the selected cats were more than 20% overweight at presentation. In all cases, the animals tolerated the procedure well. A patent stoma was created, and voluntary urination occurred within 12 hours of surgery. TPU abolished the clinical signs associated with urethral obstruction in all cases. No post-operative hematuria lasted more than 48 hours. No ambulatory disorder that might have been associated with pubic ostectomy or loss of adductor muscle attachment was observed. Urinary incontinence (UI) after urethrostomy techniques is also a major concern. Different reports indicate UI incidence rates varying from 0% to 7% after PU and from 35% to 58% after PPU [4,5,8,10,16,18]. It has been postulated that this may be due to a partial loss of urethral sphincter capacity [14-17,19,21], and the effects of PU on urethral sphincter mechanisms have been investigated using urethral pressure profiles and electro- Of the 19 cats that underwent a TPU, eight (42.1%) had some form of minor complications (that were not life-threatening), 10.5% early (before 2 months) and 31.6% later (after 2 months) (Table 1). Complications related to urethrostomy techniques in 47 Transpelvic urethrostomy (TPU) in the cat myography. One study reported a decrease in maximum urethral closure pressures one to three weeks after PU, and lack of urethral electromyographic activity post-surgically [20]. These findings indicate that perineal dissection during the PU process may damage the post-prostatic urethral musculature or its innervation. In half of the cats, however, this loss of function was reversible. Evaluation of these cats 30 to 96 months after surgery revealed that 11 out of 24 cats had regained electromyographic activity of the urethralis muscle in the postprostatic urethra and had normal maximum urethral closure pressure. Seven cats still had subnormal maximum urethral closure pressure with little if any electromyographic activity. Recommendations were made to preserve as well as possible the somatic (pudendal) and autonomic (hypogastric and pelvic) nerves during PU including taking care during section of the ischiocavernosus and ischiourethralis muscles, and blunt intrapelvic dissection sparing the most dorsal aspect of the urethra [12,13,14,18]. The benefit of such improved dissection on cystometrogram variables, electromyographic activity of the urethralis muscle, and urethral pressure profile after PU has been demonstrated [14,15]. The incidence of UI is much greater after PPU. Iatrogenic nerve damage may also occur, with additional impairment of the prepubic pre-prostatic urethral sphincter, made of smooth muscle fibres only. This internal urethral sphincter is more important in urethral competence than the striated musculature surrounding the post-prostatic urethra [14,20,21]. In all but one case, there was no UI after TPU. Our understanding of this result is that the dorsal aspect of the urethra was neither exposed nor manipulated, avoiding the risk associated with PU of damage to its innervation. Additionally, contrary to PPU, the peri-prostatic urethral internal sphincter was respected. These aspects of the TPU technique may have decreased the risk of UI. The only cat with transient UI (cured within 4 weeks) was the smallest in size and had a temporary 6-Fr catheter inserted into the urethra during the procedure. We believe that this catheter was oversized for that cat and may have irritated or distended the urethra leading to its transient incompetence. The resolution of UI after a short course of anti-inflammatory drug may corroborate this hypothesis. This anomaly lead us to stop the systematic use of a peri-operative catheter (step 1 of the technique) for subsequent cases in the series. of those recurrences was demonstrated in 1 case only, representing 5.2% of UTI after TPU. Cumulative UI and UTI rates are much higher after PPU than after PU [7-10]. In one long-term study of PPU in 32 cats, more than one third (37.5%) of them died or were euthanased because of complications associated with the procedure. Additionally, in surviving cats, owners were not satisfied because of the incidence of chronic dermatitis in the area of the inguinal fat pad [7]. The potential for postoperative complications after PPU is so high that this procedure should not be used except as a salvage procedure. Subpubic urethrostomy was proposed in 1989 as an alternative salvage procedure to remedy a failed PU [9]. The authors indicated that this technique allowed the urethrostomy site to be placed 3 cm caudal to that in the PPU technique, caudal to the inguinal fat pad, thereby alleviating the previously-reported problem of peristomal dermatitis associated with PPU. Some advantages were obvious with this technique : the portion of the urethra used for the stoma was effectively the pubic urethra, wide enough to decrease the risk of late stoma stricture, and it was far enough caudal to the prostate gland to minimise any internal urethral sphincter damage. Somehow, the transposition of the pubic urethra to a subpubic position required a manipulation of the pelvic urethra with the risk of disruption of its vascular or nerve supply. The TPU technique, as we described it originally [22] and in this paper, reproduced a similar approach to the pelvic urethra, but with no transposition. This technique placed the urethrostomy site 15 to 18 mm below the bulbo-urethral glands, 2 to 3 cm caudal to the inguinal fat pad. There were no major complications due to the technique itself, such as stoma stricture, persistent urinary incontinence, or peristomal dermatitis. The pubic urethra was entered and easily sutured to the skin without any undue tension, creating a large stoma with little risk of healing stricture. Urine passed freely through the urethral meatus with no evidence of symptomatic stricture in all cats, at short and long-term re-examinations. The dorsal aspect of the urethra was neither exposed nor manipulated, avoiding the risk associated with the other urethrostomy techniques of damage to its innervation. Additionally, contrary to PPU, the peri-prostatic urethral internal sphincter was respected. These aspects of the transpelvic technique may have decreased the risk of UI and possibly UTI. The incidence of urinary tract infection (UTI) after PU and PPU seems to be multifactorial in origin. In a study of 18 cats undergoing PU, six cats had UTI after an average follow-up of 61 months. Two of them had normal urethral pressures whereas four had low urethral pressures. There was no significant difference in incidence of bacterial UTI between cats with normal or low urethral pressures [20]. Finally, factors other than loss of urethral function may be involved in predisposing cats to bacterial urinary tract infection after perineal urethrostomy, such as the underlying uropathy combined with the exposure to nosocomial contaminants and pre-surgical urethral catheterisations [14,20,21]. In PPU, the incidence of postoperative UTI is much higher: infection rates vary from 10% to 35% after PU, and from 22% to 75% after PPU [8,10,15-18]. In our studied population, 3 cats presented with late postoperative episodes of LUTD associated with hematuria and dysuria. The bacterial origin The feasibility of the TPU technique and its promising longterm outcome may encourage the surgeon to use this technique in male cats suffering from unrelievable obstructive LUTD. As a salvage method after a failed PU, TPU should be preferred to a PPU that is associated invariably with high complication rates. TPU may also be used as a primary method of urinary diversion, as an alternative to PU, because it warrants a true approach to the pubic urethra (needed to generate a large stoma), with no dorsal peri-urethral tissue manipulation, thus reducing potential nerve damage. 48 A. BERNARDE, E. VIGUIER EJCAP - Vol. 16 - Issue 1 - April 2006 REFERENCES [12] JOHNSON (D.E.) (1974) - Feline urethrostomy: A critique and a new method. J Small Anim Pract, 15:421-425. [13] GREGORY (C.R.), VASSEUR (P.B.) (1983) - Long-term examination of cats with perineal urethrostomy. Vet Surgery, 12:210-212. [14] WILSON (G.P.), KUSBA (J.K.) (1983) - Perineal urethrostomy in the cat. In : Current Techniques in Small Animal Surgery, Second edition (Bojrab MJ, Edr), Lea & Febiger, Philadelphia, 325-333. [15] HOSGOOD (G.), HEDLUND (C.S.) (1992) - Perineal urethrostomy in cats. Comp Cont Educ Pract Vet, 14:1195-1205. [16] GRIFFIN (D.W.), GREGORY (C.R.) (1992) - Prevalence of bacterial urinary tract infection after perineal urethrostomy in cats. J Amer Vet Med Assn, 200:681-684. [17] SMITH CW, SCHILLER (A.G.) (1978) - Perineal urethrostomy in the cat: A retrospective study of complications. J Amer Anim Hosp Assn, 14:225-228. [18] GRIFFIN (D.W.) et coll (1989) - Preservation of striated-muscle urethral sphincter function with use of a surgical technique for perineal urethrostomy in cats. J Amer Vet Med Assn, 194:10571060. [19] WILLIAMS (J.M.), WHITE (R.A.S.) (1991) - Tube cystostomy in the dog and cat. J Small Anim Pract, 32:598-602. [20] GREGORY (C.R.), VASSEUR (P.B.) (1984) - Electromyographic and urethral pressure profilometry: Long-term assessment of urethral function after perineal urethrostomy in cats. Am J Vet Res, 45:1318-1321. [21] CULLEN (W.C.) et coll (1983) - Morphometry of the male feline pelvic urethra. J Urol, 129:186-189. [22] BERNARDÉ (A.), VIGUIER E (2002) - Transpubic urethrostomy in 11 cats using a caudal pubic ostectomy. Oral communication. 11th annual Scientific meeting ECVS 2002 (abstract), Vet Surgery 31:298. [1] OSBORNE (C.A.) et coll (1996) - Feline lower urinary tract disorders: Definition of terms and concepts. Vet Clin N Am, Small Anim, 26:169-179. [2] SMITH (C.W.) (1993) - Surgical diseases of the urethra. In: Textbook of Small Animal Surgery, Second edition (Slatter D, Edr), WB Saunders, Philadelphia, 462-1473. [3] CARBONE (M.G.) (1971) - Urethral surgery in the cat. Vet Clin N Am, Small Anim, 1:281-298. [4] CAYWOOD (D.D.), RAFFE (M.R.) (1984) - Perspectives on surgical management of feline urethral obstruction. Vet Clin N Am, Small Anim, 14: 677-690. [5] WILSON (G.P.), HARRISON (J.W.) (1971) - Perineal urethrostomy in cats. J Amer Vet Med Assn, 159:1789-1793. [6] BLAKE (J.A.) (1968) - Perineal urethrostomy in the cat. J Amer Vet Med Assn, 152:1499-1506. [7] MENDHAM (J.H.) (1970) - A description and evaluation of antepubic urethrostomy in the male cat. J Small Anim Pract, 11:709-721. [8] Mc CULLY (R.M.) (1955) - Antepubic urethrostomy for the relief of recurrent urethral obstruction in the male cat. J Amer Vet Med Assn, 126:173-179. [9] ELLISON (G.W.) et coll (1989) - Subpubic Urethrostomy to salvage a failed perineal urethrostomy in a cat. Comp Cont Educ Pract Vet, 11:946-951. [10] BAINES (S.J.) et coll (2001) - Prepubic urethrostomy: A long term study in 16 cats. Vet Surgery, 30:107-113. [11] KUSBA (J.K.), LIPOWITZ (A.J.) (1981) - Repair of strictures following perineal urethrostomy in the cat. J Amer Anim Hosp Assn, 17:422-433. 49 COMMISSIONED PAPER T he safe use of cytotoxic drugs in companion animal practice N. Bexfield(1) S U M M A R Y Chemotherapy has become a commonly used and accepted cancer treatment modality in companion animal practice. Clients are increasingly well informed about treatment options available for their pets, and there is pressure on veterinary surgeons to use cytotoxic drugs (fig. 1). Yet, to many veterinary surgeons, the use of cytotoxic drugs remains an unfamiliar and complex subject. Cytotoxic drugs (also known as chemotherapy, anticancer, antitumour or antineoplastic drugs) are potent and potentially dangerous, not only to the patient, but to those involved in their administration. This article addresses the safety aspects of storing, preparing and administering cytotoxic drugs in a companion animal practice setting. Potential side-effects resulting from the use of cytotoxic drugs are also described. OVERVIEW This paper was commissioned By FECAVA for publication in EJCAP The main indications for cytotoxic drugs in veterinary medicine are as first line treatment for lymphoproliferative and myeloproliferative disorders including lymphoma (lymphosarcoma), leukaemia and multiple myeloma. These diseases are systemic in nature and usually respond favourably to cytotoxic drugs. Cytotoxic drugs are of limited value as sole agents in the management of large solid tumours. They do however have a palliative role as adjuncts to surgery or radiotherapy in the prevention or management of metastatic disease associated with certain tumours. Cytotoxic drugs in combination protocols are usually preferred, as combining different drug classes with differing mechanisms of action can increase tumour cell kill without increasing toxicity. Intermittent or pulse dosing is the usual method of cytotoxic drug delivery, because continual administration of low doses will select for tumour resistance. Risks to those handling cytotoxic drugs Many of the safety issues discussed in this article should be considered in respect to individual practice facilities and staff expertise. A practice policy should be established on cytotoxic drug administration to enable consistent decision making Fig. 1: A selection of the cytotoxic drugs used in companion animal practice, all of which pose a potential risk to personnel involved in their handling. NOTE: None of the cytotoxic drugs discussed in this article are licensed for veterinary use. Owners should be suitably informed, and appropriate written consent obtained. All of these agents are potentially hazardous to the patient and to persons handling them. While every effort has been made to ensure that the drug selection and dosages in this article are in accordance with current recommendations and practice, veterinary surgeons who prescribe such drugs to patients under their care must assume responsibility for their use and safe handling. (1) Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, GB-CB3 0ES. E-mail: [email protected] 51 The safe use of cytotoxic drugs in companion animal practice Fig. 2: High visibility cytotoxic warning tape. regarding the use of specific drugs. Some practices may decide not to administer any cytotoxic drugs, while others may opt for the safe administration of a select few. Referral to a veterinary oncologist should also be considered at an early stage. Cytotoxic drug handling is acknowledged as an occupational hazard. Many of the cytotoxic drugs used in veterinary medicine are irritant to the skin and mucous membranes and also have mutogenic, teratogenic or carcinogenic properties. Human patients have been shown to develop secondary cancers as a result of treatment with cytotoxic drugs, and such risks may be acceptable when patients have a life-threatening illness. However, these effects are not acceptable to personnel involved in the reconstruction and administration of cytotoxic drugs. A number of studies have identified the presence of cytotoxic drugs and their metabolites in the serum and urine of cytotoxic drug handlers. The risks associated with occupational exposure to cytotoxic drugs are small when compared with patients treated therapeutically, but are far less understood. Exposure to cytotoxic drugs can occur in several ways: – Drugs can be absorbed through the skin, although with the majority of compounds there is little or no absorption. Skin exposure can also be by contact with contaminated equipment used in preparing or administering drugs. – Drugs can be ingested in contaminated food. – Aerosolised drugs can be inhaled during reconstitution or administration. – Accidental inoculation of drugs can occasionally occur, especially during recapping of used needles. – Metabolites can be excreted in the faeces or urine for up to 48 hours after administration. All cytotoxic drugs must therefore be handled with extreme care and in the full knowledge of their potential dangers. such as spill kits. In other European countries, occupational health and safety issues are addressed by the European Agency for Safety and Health at Work. They provide good practice guidelines for the majority of European countries similar to those of COSHH, and information can be found at http://agency.osha.eu.int/info. Individual companion animal practices should perform a risk assessment, and local rules and standard operating procedures, similar to those used for radiation protection, should be drawn up. As well as records in case-notes, separate records of all cytotoxic drugs administered should be kept. These should include details of the patient, drug and dose used, method of administration and staff involved in the procedure. A separate record book should be kept detailing stock control of cytotoxic drugs and any incidents such as spillages. Material safety data sheets of all cytotoxic drugs used in the practice should be obtained. These provide information on the physical, chemical and toxicological properties of the drug, as well as storage and handling instructions, and are distinct from the data sheets accompanying the product. All staff involved in the handling of cytotoxic drugs, from stock control to administration should receive copies of both the local rules and standard operating procedures and also be provided with suitable training. Storage Many of the common oral and injectable preparations require refrigeration; these agents should ideally be stored in a designated fridge. If this is not possible they should be kept well away from food substances in a separate clearly labelled area of the fridge. The use of high visibility “cytotoxic” warning tape is recommended (fig. 2). Where practices have multiple drug dispensing sites, such as in each consultation room, cytotoxic drugs should be kept in the main pharmacy, ideally in a separate locked area, and only dispensed by designated personnel (fig. 3). Rules and regulations In general, cytotoxic drugs are hazardous substances, and guidelines exist on their safe use in the workplace. In Great Britain, they are defined by the Control of Substances Hazardous to Health Regulations 2002 (COSHH). Some are also considered carcinogenic and are therefore subject to Appendix 1 of the COSHH Approved Code of Practice (ACOP) which provides additional guidance on the control of carcinogenic substances. Information on COSHH guidelines can be found at http://www.hse.gov.uk/coshh/. Under COSHH, employers are obliged to identify substances which are a hazard to staff, as well as those who may be exposed, how cytotoxic drugs should be handled and what to do in the event of a spill or accident. They also ensure that staff have access to the ideal environment, protective clothing, policies and procedures, a system of monitoring and recording effects and any necessary equipment Protective clothing Under the Personal Protective Equipment at Work Regulations 1992, personal protective equipment (PPE) should be provided and used whenever there are risks to health and safety. The level of protection required depends on the procedure being undertaken, and when handling cytotoxic drugs should include: – Gloves: Gloves should be worn at all times. No type of glove is completely impermeable to every cytotoxic agent, and there is no consensus as to which glove material offers the best protection; thicker gloves generally give better protection than thin ones. Using poor-quality low-cost gloves is neither safe nor cost effective. The gloves used at the author’s institution are designed for use with cytotoxic drugs and the thickness 52 N. BEXFIELD Fig. 3: If possible, cytotoxic drugs should be kept in a separate locked cabinet. EJCAP - Vol. 16 - Issue 1 - April 2006 Fig. 4: Gloves and arm sleeves should be worn at all times when handling cytotoxic drugs. increases from 0.25mm at the cuff to 0.4mm at the fingertips (fig. 4). Powder free gloves should not be used as powder can absorb cytotoxic drugs. Double gloving is unnecessary and only required when dealing with a spill. – Arm sleeves: Non-permeable polyproylene arm sleeves (0.25 – 0.35mm thick) with tight fitting cuffs should be worn at all times when working with cytotoxic drugs (fig. 4). – Gowns: Disposable gowns should be worn for both reconstitution and administration. These should be long sleeved and water resistant. Alternatively, in some situations, arm sleeves and plastic aprons can be substituted for longsleeved gowns during drug handling. – Eye protection: Goggles are used to protect the eyes from splashes and particles and should fully cover the eyes to protect the handler (fig. 5). They are not required when work is being done in a safety cabinet, but should be worn at all other times. – Masks: Respiratory protective equipment (RPE) is required if drugs are to be prepared outside a safety cabinet. These should also be worn whenever there is a possibility of inhalation of the drug during administration. Disposable paper surgical type masks offer no respiratory protection, but may help avoid mucosal contamination. Fig. 5: Different types of eye protection used when handling cytotoxic drugs. It is unlikely that the majority of practices will have biological safety cabinets. Preparation of drugs without such equipment is therefore a compromise on safety, but may be acceptable if only occasional treatments are given. In this situation drugs should be prepared in an area away from people and animals, without doors, windows or draughts, and the maximum possible personal protection used. This should include gloves, disposable arm sleeves and a gown, goggles and a mask (see above). Fig. 6: Drugs should be prepared in a biological safety cabinet is possible. A disposable absorbent mat protects horizontal surfaces from accidental spillage. Drug preparation Ideally drugs should be prepared in a biological safety cabinet, which are categorised based on the level of protection they offer (fig. 6). They offer protection to the operator (class 1), the operator plus the drug based on airflow (class 2), or are designed as a complete sealed unit to offer both drug and operator protection (class 3). In all of these systems, air is filtered through special particle absorbers before being discharged into the atmosphere or back into the room. Conventional laminar airflow cabinets are unsuitable as airflow, hence droplets, is directed towards the operator. The same is true for fume-hoods which merely alter local airflow. 53 The safe use of cytotoxic drugs in companion animal practice Fig. 7: Appropriate equipment minimizes Fig. 8: Tablets should be dispensed in their original containers, or staff exposure to cytotoxic drugs. Here a repackaged in child-proof filtered venting device and leur lok containers and clearly labelled syringe are used to prevent aerosol as cytotoxic drugs. formation. Some basic rules when preparing cytotoxic drugs should be followed. These refer to liquid or powder for reconstitution cytotoxic drugs: Fig. 9: Cytotoxic drugs can be formulated as a solution for injection or powder for reconstitution. contamination of people or work surfaces. All staff involved in handling cytotoxic drugs should be familiar with such procedures, and these should be readily available for emergency use. The following procedure should be followed when dealing with a spillage: 1. Put on a double pair of gloves, gown, disposable plastic apron over the gown, arm sleeves and goggles. 2. If there is visible powder spill, put on a suitable respiratory mask. 3. If spillage is on the floor, put on overshoes. 4. Wipe up any powder spillage quickly with well damped paper towels. 5. Mop up liquids that have been spilt on hard surfaces with paper towels, starting at the outer edge of the spill area and working in a circular motion towards the middle of the spill. 6. Wash hard surfaces at least twice with copious amounts of cold, soapy water and dry with paper towel. 7. If there is direct skin contact, the area should be washed thoroughly with soapy water as soon as possible and for at least two minutes. Eye wash should be used if necessary. 8. All contaminated materials should be disposed as cytotoxic waste. – Drugs should be prepared by trained staff in a designated area. – All preparation surfaces, even in a biological safety cabinet should be covered by a plastic backed-absorbent mat. – The use of ready-to-use formulations in rubber stoppered bottles avoids the need for reconstitution. – Air must never be injected back into the bottle, nor should syringes containing air be vented into the atmosphere. If it is necessary to expel air from a filled syringe it should be exhausted into an absorbent pad. – The use of commercial filters to prevent the ventilation of toxic aerosols should be considered (fig. 7). These help equalise the pressure during reconstitution and as drugs are being drawn up. – Regular hypodermic needles placed into the stopper as an air vent should not be used. – Leur lok type syringes can be used to prevent accidental separation of the needle from the syringe or syringe from the venting device or container (fig. 7). – All intravenous lines should be primed prior to addition of cytotoxic drugs to infusion bags. – After preparation, drugs should be placed in a labelled, sealable plastic bag to contain any spills during transport to the area where the drug is to be administered. Administration of cytotoxic drugs Cytotoxic drugs are commonly available in two forms: – Tablets or capsules for oral administration. – Powder for reconstitution or solution for injection. The following guidelines should be followed to enable the safe handling of cytotoxic drugs: Alternatively, some human hospital pharmacies and private companies will dispense cytotoxic drugs formulated at the correct dose and ready for administration. If available, this facility is a convenient and safer option to drug preparation in some veterinary practices. 1. ORAL The oral route of drug administration is convenient, economical, non-invasive and sometimes less toxic than other routes. Most oral drugs are well absorbed if the gastrointestinal tract is functioning normally. However, in some situations drug delivery by this route is not possible. Several basic recommendations should be followed when dispensing or administering tablets or Cytotoxic drug spillages Veterinary practices should have clear procedures, based on risk assessment, in place for dealing with spillages or 54 N. BEXFIELD EJCAP - Vol. 16 - Issue 1 - April 2006 capsules by the oral route: – Tablets should NEVER BE CRUSHED OR BROKEN and capsules should NEVER BE OPENED. – Safe dosing schedules can be devised for most drugs, by increasing the inter-dosing interval, sourcing an alternative formulation or using an injectable preparation. – It is sometimes possible for drugs to be specially compounded by a local pharmacy or hospital pharmacy. – Disposable latex gloves should be worn when handling any tablet or capsule. – When tablets or capsules are provided in an individual wrapper, they should be dispensed in this form. – Tablets and capsules should be dispensed without altering the manufacturers’ packaging where possible, but should always be dispensed in child proof containers. – Tablets should be counted using a triangle which should be washed and dried after use. – In addition to the statutory requirements for the correct labelling and dispensing of medicinal products, all containers should be child proof and clearly labelled. The use of highly visible tape with the “cytotoxic” warning is encouraged (fig. 8). – If tablets and capsules are given in food, ideally they should be mixed with a small amount of food to ensure ingestion. – If administered to the animal directly per os, care should be taken to avoid accidental spillage or dissolution of the outer protective covering. – Hands should always be washed after handling any drugs. – Staff and owners should receive clear instructions on the administration of oral medication, and an information leaflet is useful for this purpose. Owners should be made aware of the potential hazards when administering these medications, and also be provided with a supply of gloves. – Unused medications should be returned to the veterinary practice for disposal. cytotoxic’s, some of which are presented as freeze-dried material or powder, requiring to be mixed with diluents (fig. 9). Potential dangers in the handling and manipulation of these products include the creation of aerosols during reconstitution and accidental spillage. Intravenous drugs can be administered via a traditional preplaced over-the-needle catheter or butterfly-style catheter (fig. 10). Off the needle administration of any drug, no matter how small the volume, is strongly discouraged. The following basic steps should be followed, some of which apply to drugs administered as an infusion: – Adequate restraint should be considered if the animal is fractious or infusion times are long. – The large veins of the forelimb (cephalic) should be chosen for i.v. access, as they are the easiest, reduce the risk of chemical phlebitis and result in fewer problems if extravasation should occur. – Butterfly style catheters should not be used when the volume of drug is greater than 2mls or the drug is given as an infusion (e.g. doxorubicin as an infusion). Potentially vesicant drugs should also not be given via butterfly catheters because of the increased risk of dislodgment over conventional catheters. – The general rule is to start catheter placement distally and proceed proximally where possible. – Alternate the legs to ensure the same veins are not being used and damaged by chemical and mechanical irritation. – Patency should be checked by achieving blood return followed by flushing with 10ml of 0.9% sodium chloride to ensure there is no resistance, swelling or pain. Heparin saline should be avoided as it can precipitate some drugs, especially doxorubicin. – Catheters should be firmly taped in placed after verification of patency (fig. 11). – The catheter site should not be covered. – During drug administration the catheter site should be checked periodically and administration of the drug stopped if resistance is felt, swelling occurs or there are signs of a local or generalised reaction – If the drug is given as an infusion, 20mls of saline can be 2. INTRAVENOUS The main risk for cytotoxic drug exposure to personnel arises during the preparation and administration of injectable Fig. 11: Drugs for intravenous injection should be administered via a securely placed intravenous catheter. (Courtesy of Dr J Dobson, The University of Cambridge) Fig. 10: A dog receiving cytotoxic drugs. Note the use of an absorbent mat and swabs to absorb any leaked drug. (Courtesy of Dr J Dobson, The University of Cambridge) 55 The safe use of cytotoxic drugs in companion animal practice Disposal added to the empty bag after the infusion has finished thereby removing residual drug. – After the infusion is complete, the catheter and any ports should be flushed with at least 10mls of saline, and the catheter removed immediately. – All materials should be placed into a sealed plastic bag and discarded as cytotoxic waste. Suitable containers, clearly labelled and reserved solely for the use of cytotoxic waste should be available (fig. 12). Waste should be disposed of by high temperature chemical incineration by a licensed authority. Practices should consult their waste disposal provider for more specific details of cytotoxic drug waste disposal. The following general guidelines apply: – Sharps should be placed in an impermeable plastic container specified for cytotoxic waste. Absorbent matting should be placed in the bottom of the sharps bin to absorb any leakage. Used needles should never be recapped as this greatly increases the risk of accidental self injection. – Solid waste (e.g. contaminated syringes, giving sets, catheters, fluid bags, absorbent paper, gloves, aprons, e.t.c.) should be double wrapped and sealed in labelled polythene bags (fig. 13). The sealed bags are then placed in cytotoxic waste bins. – Empty drug containers and vials containing less than 1ml of solution may be treated as “solid waste”. – Excess or out of date drugs, tablets or solutions should be disposed of in cytotoxic bins for DOOP (Destruction of Old Pharmaceuticals). They must be double wrapped, sealed in polythene bags, and clearly labelled with the drug name and amount remaining. NB: Peripheral veins should be avoided for routine blood collection from oncology patients, and the jugular vein used instead. 3. INTRAMUSCULR AND SUBCUTANEOUS Only a few cytotoxic drugs can be administered by this route due to several factors including their irritant nature, incomplete absorption, bleeding as a result of paraneoplastic thrombocytopenia and discomfort at the injection site. Drugs administered in this way include: – Cytosine arabinoside – L-asparaginase – Methotrexate – Bleomycin Animals should be adequately restrained for administration of drugs by this route if the volume administered is large or the drug is likely to be painful (L-asparaginase). Suitable gloves and other protective equipment should be worn during the procedure, as there is greater potential for spillage. After insertion of the needle, aspiration should be performed to make sure a blood vessel has not been inadvertently entered. Animals can excrete potentially harmful drugs or drug metabolites in their urine, faeces, vomit or saliva for variable time periods after administration. Steps should be taken to minimise this exposure: 1. All patients should be clearly identified as receiving or having received chemotherapy (fig. 14). This is particularly important for in-patients, which may be cared for by staff who were not present when cytotoxic drugs were given. 2. Owners should be made aware of the potential risks of contaminated waste from their pets. Often little more than normal hygiene precautions are required, but specific 4. INTRACAVITARY ADMINISTRATION Occasionally some drugs including carboplatin and cisplatin are administered into a body cavity. Due to the potential hazards associated with this route of administration, and the specialised technique required, the clinician is encouraged to consult a veterinary oncology specialist before undertaking this procedure. Fig. 12: Containers for cytotoxic waste should be specific for that purpose and clearly labelled. Fig. 13: Solid waste should be sealed in labelled polythene bags before being placed in cytotoxic waste bins. 56 Fig. 14: Kennels containing in-patients receiving cytotoxic drugs should be clearly marked, as staff providing ongoing care may have been absent during drug administration. N. BEXFIELD EJCAP - Vol. 16 - Issue 1 - April 2006 instructions should also be given. 3. Solid waste and small amounts of absorbent material can be flushed down the toilet. 4. Other waste should be doubled bagged and placed in the domestic waste. 5. Dogs should be encouraged to urinate on grass, and urine should be hosed of hard surfaces using care to avoid splashes. have documented moderate to severe myelosuppression following single-agent vincristine therapy in occasional patients. Cells with the shortest life span are most susceptible; therefore myelosuppression is commonly manifested by a decrease in the neutrophil count. Mild neutropenia is relatively common and not often a clinical problem, but severe neutropenia can result in an increased risk of infections and sepsis. The neutrophil nadir is usually 7-10 days for the majority of drugs, although there is some patient variation. Most combination drug protocols are designed to allow complete bone marrow recovery prior to the administration of the next round of treatment. Several factors affect the risk and outcome of infection, the most important of which are severity and duration of neutropenia. Animals should be considered at risk of opportunistic infections when the neutrophil count fall to less than 2.0 x 109/l. Organisms most frequently isolated are Gram-negative enteric bacteria followed by Gram-positive cocci. Common sites of infection are the blood stream (bacteraemia) and the lungs. It is important to remember that severely neutropenic patients may not show the classic signs of infection, due to the lack of cells required to produce an inflammatory response. For instance, neutropenic animals may exhibit a normal or even subnormal temperature. Diagnostic tests performed in the symptomatic neutropenic patient should include a complete blood count (CBC), serum biochemistry and urinalysis. Other tests such as thoracic radiography, urine or blood culture may also be required. COMPLICATIONS OF CHEMOTHERAPY Toxicity is the most important and major treatment-limiting factor in chemotherapy. Cytotoxic drugs are not selective in their actions on growing or dividing cells, hence organs that contain a high proportion of dividing cells, for example the bone marrow or gastrointestinal tract, are particularly susceptible to these toxic effects. Complications can arise at any time during cytotoxic drug administration, and some agents can induce immediate hypersensitivity reactions, while others cause longer term sideeffects. Although potentially life threatening, these toxic effects are usually reversible on discontinuation of treatment. Some cytotoxic drugs have other toxic actions that are unfortunately less reversible. These include doxorubicin (cardiotoxicity), cyclophosphamide (sterile haemorrhagic cystitis) and cisplatin (nephrotoxicity). Discussed below are some of the more common side-effects applicable to veterinary cancer patients: There are two main scenarios during cytotoxic drug treatment when a veterinary surgeon may be faced with a neutropenic animal: 1. An ill animal presenting several days after administration of a cytotoxic drug. 2. Routine blood sampling prior to the next dose of a cytotoxic drug in an otherwise asymptomatic animal. The response to these two scenarios varies. Withholding cytotoxic drug administration for 5-7 days, in combination with 1. Bone marrow suppression and infections. Myelosuppression is the most common and potentially serious side-effect resulting from the use of cytotoxic drugs, and is the main dose-limiting factor in veterinary chemotherapy. Most drugs are myelosuppressive, although there are a couple of exceptions, namely vincristine and L-asparaginase. Recent reports however Table 1. Management of cytotoxic drug-induced Neutropenia. Neutrophil count (x 109/l) Status of patient Recommended action >3 Asymptomatic/ afebrile 2-3 Asymptomatic/ afebrile <2 Asymptomatic/ afebrile Continue cytotoxic drugs Repeat CBC in 3 weeks Reduce dosage of myelosuppressive drugs by 50% Repeat CBC in 1-2 weeks Stop cytotoxic drugs, and repeat CBC in 1 week. If patient has a potential source of infection, such as an ulcerated tumour, administer prophylactic antibiotics Stop cytotoxic drugs. Start antibiotics (oral route usually sufficient). Monitor patient carefully for deterioration and repeat CBC in several days Stop all cytotoxic treatment and monitor carefully. Administer antibiotics (oral route usually sufficient). Repeat CBC in several days Hospitalise Supportive therapy (intravenous fluids, electrolytes etc) Intravenous antibiotics Consider sampling patient to identify infective agent Symptomatic <1 Asymptomatic/ afebrile Symptomatic 57 The safe use of cytotoxic drugs in companion animal practice careful monitoring, is usually all that is required when faced with an asymptomatic neutropenic animal. An ill neutropenic animal requires more aggressive management, including the administration of broad spectrum antibiotics and other supportive measures. Table 1 outlines the suggested management of neutropenic patients. 48 hours prior to anticipated chemotherapy induced neutropenia, and appears to reduce the duration and severity of neutropenia. Recent evidence suggests it is not beneficial in the treatment of established afebrile or febrile neutropenia. Only a human recombinant product is available and there is therefore the potential for cross-reactive antibody production. Notes on antibiotic use in the neutropenic patient: – Antimicrobial therapy is directed at the intestinal flora, with the principal objective of reducing the Gram-negative and Gram-positive organisms most often responsible for infections. The intestinal anaerobic population should be left relatively undisturbed since it helps prevent colonization by contagious bacteria, fungi and yeast. – In most cases the choice of antibiotic is empirical, but should be bactericidal and broad-spectrum. – Suitable choices for the treatment of the asymptomatic neutropenic patient included potentiated sulphonamides or fluoroquinolones. – Suitable choices for the treatment of the ill neutropenic animal include the INTRAVENOUS administration of: – A penicillin and aminoglycoside. – A cephalosporin and aminoglycoside. – A penicillin or cephalosporin and a fluoroquinolone (the author’s choice). – A second or third generation cephalosporin alone. – Impipenem-cilastin or other carbapenems used alone. NB: Aminoglycosides should not be administered to any animal with renal compromise, and animals should be adequately hydrated prior to their use. NB: Fluoroquinolones should be avoided in skeletally immature animals because of the possibility of inducing cartilage damage. 2. Gastrointestinal toxicity The most common problem noted by pet owners following the administration of cytotoxic drugs is gastrointestinal toxicity, manifested as anorexia, vomiting and diarrhoea. In most cases these side-effects are transient and spontaneous recovery occurs as the gastrointestinal tract epithelium regenerates. Some drugs including cisplatin and doxorubicin induce nausea and vomiting within a few hours of drug administration, or these signs may be delayed, occurring after 48 hours or later. Most other cytotoxic drugs used in veterinary medicine cause delayed vomiting. Anti-emetics commonly used in the prevention of cytotoxic drug induced nausea and vomiting include: – Metoclopramide (0.5-1.0 mg/kg i.m., s.c., p.o. q6-8hrs) - the most commonly used anti-emetic, and has both central and peripheral effects. – Butorphanol (0.2-0.6mg/kg s.c.)- particularly useful with cisplatin chemotherapy. – Chlorpromazine (0.5mg/kg i.m. or s.c. q 6-8hrs) - used for mild nausea and is centrally acting. – Ondansetron (0.5mg/kg i.v. loading dose followed by 0.5-1.0 mg/kg p.o. q12-24hrs) - a very effective, although more expensive anti-emetic. Treatment of gastrointestinal complications is symptomatic and includes intravenous fluid therapy, anti-ulcer and anti-emetic drugs: – Mild signs can usually be managed by withholding food and water, and if the animal is vomiting, by providing an antiemetic. – Severe gastrointestinal toxicity lasting for more than 36 hours and not responding to oral anti-emetic therapy should be treated aggressively. – Severe gastrointestinal mucosal injury can predispose to bacterial translocation, and parenteral antibiotics may be required. Notes on the use of prophylactic antibiotics: – Antimicrobial prophylaxis use is controversial in both human and veterinary oncology. – Routine prophylactic therapy during cytotoxic drug use is not recommended if the owner can closely observe the animal, and if the anticipated neutropenia is of short duration. – Prophylactic antibiotics should be considered in the asymptomatic patient whenever a neutrophils count is less than 1.0 x109/l. – Prophylactic antibiosis is most likely to be beneficial during severe, prolonged neutropenia. – Animals that have had a previous episode of cytotoxic drug induced sepsis should be given prophylactic antibiotics during additional treatment (in combinations with a reduced dose of cytotoxic drugs). – Prophylactic antibiotics have the potential to induce gastrointestinal side-effects and the development of resistant organisms. Prophylactic antibiosis is particularly discouraged in cats which are less at risk of infections secondary to neutropenia than are dogs, but are more at risk of antibioticinduced gastrointestinal disorders. 3. Extravasation Some cytotoxic drugs are vesicants and can induce serious sideeffects if they leak out of the vein or are extravasated (fig. 15). In veterinary medicine the most common drugs to cause this reaction are vincristine, vinblastine and doxorubicin. The severity of the reaction is dependant on the agent and the volume that leaks into the surrounding tissues. Clinical signs range from pain, erythema, swelling and moist dermatitis, to severe skin sloughing. Signs tend to be delayed occurring after approximately 1-7 days (vincristine/vinblastine) or 7-10 days (doxorubicin). In the event of perivascular leakage of a vesicant drug, the following general guidelines should be followed: – Stop the infusion. – Leave the catheter in place. Notes on Granulocyte colony stimulating factor (GCSF). GCSF is a haematopoietic cytokine, which acts primarily to stimulate the proliferation and maturation of neutrophil precursors. It is most beneficial when given prophylactically 24- 58 N. BEXFIELD EJCAP - Vol. 16 - Issue 1 - April 2006 Fig. 17: Cats rarely develop severe Fig. 15: Early tissue necrosis following alopecia but may lose their perivascular administration of whiskers after cytotoxic drugs. doxorubicin in a dog. (Courtesy (Courtesy of Dr J Dobson, The of Dr J Dobson, The University of Fig. 16: Owners should be warned about the possibility of University of Cambridge) Cambridge) alopecia following the use of certain cytotoxic drugs. – Try to aspirate any remaining drug and blood from the catheter, although this is often not possible. – Remove the catheter. – Administer soluble corticosteroids systemically (intravenous), locally (subcutaneous) and topically (cream) around the site of extravasation. Specialist help from a veterinary oncologist should also be sought as early as possible. – Doxorubicin can induce mast cell degranulation, therefore slowing the infusion and pre-treating with anti-histamines and glucocorticoids can eliminate or lessen the effects. Treatment of hypersensitivity reactions is the same for any drug and includes the following: – Discontinue the infusion. – Administer anti-histamines and glucocorticoids intravenously. – Give intravenous fluids and adrenalin (epinephrine) if necessary. Specific recommendations for two of the most frequently used drugs are given below, although these guidelines are based on experience from human medicine: 5. Effects on hair coat Doxorubicin/epirubicin: – Infiltrate the area with 2 to 5 ml of 2.1% sodium bicarbonate, leave for 2 minutes and aspirate off. – Apply dimethylsulfoxide (dimethylsulphoxide, DMSO) topically to the area every 2 hours. – Apply hydrocortisone cream (or equivalent). – Apply COLD compresses. Poor hair growth or alopecia may occur, but is breed-dependent and typically occurs in breeds with growing hair such as Poodles, Old English sheepdogs and some terriers (fig. 16). Hair usually grows back when chemotherapy is discontinued, but occasionally may return with an altered consistency or colour. Cats rarely develop alopecia but may lose their whiskers (fig. 17). Owners of susceptible breeds should always be warned about these potential side-effects. Vincristine/vinblastine: – Infiltrate area with 1500 units of hyaluronidase. – Apply HEAT and compression. Several side-effects are drug specific and include: 1. Cardiac toxicity- doxorubicin Cardiotoxicity is a widely recognised side-effect of doxorubicin and can occur with short and long-term therapy. The acute form manifests as tachycardia and arrhythmias occurring during or soon after administration of the drug. The chronic form is more common and results in dilated cardiomyopathy leading to congestive heart failure (fig. 18). The mechanism of cardiotoxicity associated with doxorubicin administration is due to free radical production and subsequent oxidative damage to myocytes. Diagnosing doxorubicin associated cardiotoxicity can be difficult and unfortunately is often only performed when clinical signs of congestive heart failure are apparent. Tachyarrhythmias are the first sign to be noted, followed by echocardiographic evidence of decreased fractional shortening. There are several potential biochemical markers of ensuing cardiotoxicity under trial, and the author has preliminary data to suggest one of these, cardiac troponin-I, may be of use. Treatment of doxorubicin-induced cardiomyopathy is the same as that employed for any other type of cardiomyopathy, and the reader is referred elsewhere. 4. Allergic reactions The agents most commonly associated with hypersensitivity or allergic reactions include L-asparaginase and doxorubicin. Signs of hypersensitivity reactions include urticaria, erythema, vocalisation, restlessness, vomiting, and oedema of the head. Severe reactions can also lead to hypotension. Cats tend to exhibit similar signs, but respiratory signs such as dyspnoea or open-mouth breathing are also relatively common. Certain precautions can be employed to reduce the occurrence of hypersensitivity reactions. These include: – Administering L-asparaginase intramuscularly rather than intravenously. – Attempting to avoid repeated doses of L-asparaginase as the likelihood of hypersensitivity reactions increases after repeat treatment (due to the formation of antibodies against Lasparaginase). – Administering an anti-histamine or combination of an antihistamine and glucocorticoid prior to administration of drugs that can potentially cause hypersensitivity reactions. 59 The safe use of cytotoxic drugs in companion animal practice Fig. 18: Four-chamber echocardiographic image demonstrating dilated cardiomyopathy which may result from doxorubicin therapy. Fig. 19: Sterile haemorrhagic cystitis resulting from the use of cyclophosphamide in a dog. Owners can be provided with urine dipsticks and instructed to perform urinalysis to help prevent its occurrence. (Courtesy of Dr J Dobson, The University of Cambridge) Doxorubicin-induced cardiotoxicity can be prevented by: – Using doses no higher than the maximum cumulative dose (240mg/m2 for dogs). – Avoiding the drug in breeds with a predisposition to cardiomyopathy. – Avoiding the drug in dogs with concurrent heart disease. – Periodic monitoring for cardiotoxicity by echocardiography; at the authors institution, this is performed prior to the initial treatment and subsequently before every second or third treatment. – Monitoring pulse rate and character during doxorubicin administration and immediately afterwards. If abnormalities are detected, the infusion should be stopped or the rate decreased. – Increasing the infusion time thereby reducing peak plasma levels and cardiotoxic effects. – The concurrent use of the cardioprotective agent dexrazoxane, which chelates iron thereby preventing doxorubicin interaction and subsequent free radical formation. It is given 30 minutes prior to doxorubicin. The author does not use this drug as its availability is limited and other methods are employed to minimise cardiotoxicity. – By using alternative drugs to doxorubicin such as epirubicin. Cardiotoxicity appears to be less of a problem with this drug, although can still occur. rather than having the toxic metabolite accumulate in the bladder overnight. Ensuring a good fluid intake. Encouraging frequent emptying of the bladder. Administering prednisolone for its diuretic and antiinflammatory effects; some animals may however already be receiving prednisolone therapy as part of a multidrug protocol. Administering frusemide concurrently with cyclophosphamide has shown some benefit. Administer the bladder protective drug mesna (2mercaptoethanesulfonate). It is beneficial in the treatment of sterile haemorrhagic cystitis in humans, but its use in veterinary oncology is infrequently reported. Owners can be provided with urine dipsticks and instructed to test their animal’s urine at least once a week while on cyclophosphamide therapy. Owners should be instructed to stop cyclophosphamide if there is persistent haematuria or proteinuria. Owners should be discouraged from collecting urine in the 48 hours immediately after administration of any cytotoxic drug however. – – – – – – Clinical signs of sterile haemorrhagic cystitis are non-specific of lower urinary tract disease, and include haematuria, dysuria and pollakuria. Urinalysis typically reveals red blood cells, proteinuria and mild to moderate numbers of white cells. Urine culture at least during the early part of the disease is negative. 2. Sterile haemorrhagic cystitis- cyclophosphamide Sterile haemorrhagic cystitis is a potential side-effect of cyclophosphamide treatment in the dog and cat (fig. 19). This toxicity is more common during chronic therapy but has been reported to occur after only one treatment. Cystitis results from the toxic effects of a metabolite of cyclophosphamide, acrolein, on the bladder mucosa. There are no specific treatments for cyclophosphamide induced cystitis, although the following measures should be followed: – Discontinue the drug. – Prophylactic antibiotics to treat any secondary infections. – Anti-inflammatory drugs such as glucocorticoids or nonsteroidal anti-inflammatory drugs (the latter should not be administered to any animal already receiving glucocorticoids). – Intravesicular administration of 1% formalin or 25% DMSO has been advocated, but author has no experience with either of these treatments. Studies in large groups of dogs are also lacking, and both drugs have the potential to worsen the disease so are probably best avoided. Several measures can be taken to decrease the likelihood of sterile cystitis developing: – Administering cyclophosphamide in the morning, thereby allowing the patient to urinate frequently during the day, 60 N. BEXFIELD EJCAP - Vol. 16 - Issue 1 - April 2006 3. Hepatotoxicity- methotrexate or lomustine Ensure the giving set is primed and contains no air bubbles. – Add the required dose of drug to the bag of saline. – Place an intravenous catheter into a suitable peripheral vein, and connect a three way tap. Ensure correct placement of the catheter by flushing with a least 10mls of saline. NB do not use heparin saline as this can result in precipitation of the drug. – Tape the catheter securely in place. – Premedicate the animal with an antihistamine given by slow intravenous injection over one minute. – Connect the giving set to the three-way tap, and administer the diluted doxorubicin in the saline drip over approximately 20-30 minutes. – Monitor the animal’s heart rate, rhythm and catheter site. Stop the infusion if there are signs of anaphylaxis, arrhythmias or problems with the catheter site. – When the infusion is complete, 20mls of fresh saline can be added into the empty saline bag, and this administered to the patient to remove remaining drug residues from the infusion set. – Close off the giving set and disconnect it from the three-way tap. – Flush the catheter with approximately 10 mls of fresh saline prior to removal. – Dispose of the catheter, giving set and empty saline bag as contaminated cytotoxic waste. NB: Appropriate protective clothing should be worn during the preparation and administration of this drug (see earlier). Hepatotoxicity associated with cytotoxic drug use is rare. In human oncology patients, liver damage is most frequently associated with the use of methotrexate or lomustine. Severe hepatotoxicity has also been reported in dogs receiving lomustine chemotherapy, and it would therefore be prudent to measure liver enzymes and monitor liver function periodically during treatment with this drug. 4. Neurotoxicity- vincristine, cisplatin and 5-fluorouracil Neurotoxicity is rarely observed in small animal patients receiving cytotoxic drugs. Vincristine is reported to cause a peripheral neuropathy in dogs, manifested by hindlimb weakness. In humans, vincristine can cause a variety of nervous system effects including peripheral, central or autonomic effects, which most often occur with high, repetitive dose therapy. 5. Nephrotoxicity- cisplatin Cisplatin is the drug most associated with nephrotoxicity, although both doxorubicin and methotrexate can also cause renal damage. There is an increased incidence of clinically evident cisplatin-induced nephrotoxicity in patients with preexisting urinary tract disease. A minimum data base prior to the administration of cisplatin should therefore include a CBC, BUN and creatinine measurement and urinalysis. Various means of preventing cisplatin induced nephrotoxicity are described below. By comparison, carboplatin is not reported to be nephrotoxic in humans at normal doses, and the same is expected in small animal patients. As the kidneys are the elimination pathway for a variety of cytotoxic drugs, reduced renal function can lead to prolonged exposure of normal tissues to cytotoxic drug, thereby potentially increasing side-effects. Specific formulae, such as the CockroftGault conversion formulae are employed in human medicine to allow the dose of a wide variety of drugs to be adjusted based on renal function. Similar formulae however do not exist for small animal patients. Carboplatin: – Calculate the required dose of the drug. The usual dose is 300mg/m2. – Reconstitute the drug according to the manufactures instructions. – Place an intravenous catheter into a suitable peripheral vein, and connect a three-way tap. Ensure correct placement of the catheter by flushing with a least 10mls of saline. – Tape the catheter securely in place. – Connect an intravenous giving set to a 500ml bag of 0.9% saline. NB: do not use needles or giving sets containing aluminium as precipitation of the drug may occur. – Connect the giving set to the three-way tap and allow the saline to run in at a moderate rate. – Inject the carboplatin through the side port of the giving set over about 10 minutes while the saline is running. – Leave the saline running for several minutes after carboplatin administration. – Disconnect the giving set and remove the catheter. – Dispose of the catheter, giving set and saline bag as contaminated cytotoxic waste. NB: Some texts recommend the use of 5% glucose saline instead of 0.9% saline to reduce the risk of carboplatin being converted to cisplatin. This is more likely to be a problem however if carboplatin is mixed with saline for a prolonged period of time. CONCLUSIONS By adhering to these guidelines, the safe use of cytotoxic drugs should be possible for the majority of companion animal practices, with minimal risk to all staff involved. Practices and personnel should not become complacent with cytotoxic drug administration, and regular risk assessment and updates to local rules should be performed. Careful administration of cytotoxic drugs and subsequent monitoring is also required to avoid the many potential complications resulting from the use of these drugs. Procedures for the administration of specific drugs: Doxorubicin: – Calculate the required dose of drug. The usual dose is 30mg/m2. – Reconstitute the drug according to the manufacture’s instructions. – Connect a conventional intravenous giving set to a 500ml bag of 0.9% saline and discard approximately 200-300mls of fluid. 61 The safe use of cytotoxic drugs in companion animal practice Cisplatin: NB: cisplatin should never be administered to cats as its use results in fatal pulmonary oedema. Six hour infusion with saline diuresis: – Prehydration: Intravenous 0.9% saline at 25ml/kg/hour for 3 hours. – Cisplatin: 50-70mg/m2 given as a slow intravenous infusion over approximately 20 minutes. – Anti-emetic: metoclopramide at 1mg/kg intravenously. Alternatively butorphanol or a 5HT-3 antagonist such as ondansetron can be used. – Further diuresis: Intravenous 0.9% saline at 15ml/kg/hour for 3 hours. Infusion with mannitol diuresis: – Prehydration: Intravenous 0.9% saline at 10ml/kg/hour for 4 hours. – Mannitol: 0.5g/kg given intravenously in saline over 30 minutes. – Cisplatin: 50-70mg/m2 given as a slow intravenous infusion over approximately 20 minutes. – Anti-emetic: as above. – Further diuresis: Intravenous 0.9% saline at 10ml/kg/hour for 4 hours. Vincristine: – Calculate the required dose of drug. The usual dose is between 0.3 and 0.75 mg/m2. – Place an intravenous catheter into a suitable peripheral vein, and connect to a three-way tap. – Ensure correct placement of the catheter by flushing with a least 10mls of saline. – Tape the catheter securely in place. – Inject vincristine slowly over approximately one minute. – Flush the catheter with approximately 10mls of saline. – Remove the catheter and dispose all materials as contaminated cytotoxic waste. FURTHER READING ABRAMS-OGG (A.C.G.), KRUTH (S.A.) – Antimicrobial Therapy for the Neutropenic dog and Cat. In: Bonagura JD, editor. Kirk’s Current Veterinary Therapy. Philadelphia: W.B. Saunders Co., 2000: p.267-272. New Product Information CAN YOU HANDLE LIQUID AND POWDER CYTOTOXIC SPILLS? Helapet announces two firsts in one! Berner’s NEW Spill Kit XP is the first kit suitable to safely clean up both liquid and powder Cytotoxic spills and it is the first kit to comply with European PPE guidelines for handling cytotoxics. Every kit contains appropriate safety apparel, absorbent mats, distilled water and scoop and tongs for glass and sharp fragments, as well as packaging for disposal. With easy to follow instructions, units can rest assured that spills can be dealt with quickly and efficiently whilst offering maximum protection to the operator. For more information, contact our friendly sales team on 0800 0328 428, or visit our website at www.helapet.co.uk ALLWOOD (M.), STANLEY (A.), WRIGHT (P.) – The Cytotoxics Handbook. 4th edition, Ratcliffe Medical Press, 2002. CHUNN (R.), GARRETT (L.), MACEWEN (E.G.) - Cancer chemotherapy. In: Withrow SJ and MacEwen EG, editors. Small Animal Clinical Oncology. Philadelphia: W.B.Saunders Co., 2001:p.92-118. DOBSON (J.M.), GORMAN (N.T.) - Cancer Chemotherapy in Small Animal Practice. Blackwell Scientific publications, 1993. HANN (K.A.), RICHARDSON (R.C.) – Cancer Chemotherapy. A Veterinary Handbook. Baltimore, Williams and Wilkins, 1995. LANA (S.E.) – Chemotherapy. In: Dobson JM and Lascelles BD, editors. BSAVA Manual of Canine and Feline Oncology. BSAVA Publications, 2003: p. 86-103. NEWMAN (M.A.), VALANIS (B.G.), SCHOENY (R.S.) HEE (S.Q.) – Urinary biological monitoring markers of anticancer drug exposure in oncology nurses. Am J Public Health, 1994, 84:852855. VALANIS (B.), VOLLMER (W.M.), STELE (P.) – Occupational exposure to antineoplastic agents: self-reported miscarriages and still births among nurses and pharmacists. J Occup Environ Med, 1999, 41:632-638. COSHH. Control of Substances Hazardous to Health Regulations 2002. Approved Code of Practice and Guidance (fourth Edition HSE books ISBN 0 7176 2534 6). Safe Handling of cytotoxic drugs. HSE information Sheet MISC615. Some of the many manufacturers supplying protective equipment for the safe use of cytotoxic drugs: Helapet Limited, Circle Business Centre, Blackburn Road, Houghton Regis, Bedfordshire, LU5 5DD, UK. Chemoprotect® protection system, supplied by Codan Limited, Eastheath Avenue, Wokingham, Berkshire, RG41 2PR, UK. COMMISSIONED PAPER T he future of Biomarkers and Personalised Medicine in Companion Animal Practice S. Mian(1)( 2), K. Slater(1), T.Cave(3) S U M M A R Y The ability to utilise a patient’s own genetic expression information to detect the onset of disease, monitor its progression and even suggest possible treatment modalities which have the highest probability of success would undoubtedly provide a mechanism in which to enhance the quality of care and treatment for companion animals. As with all clinical situations, veterinarian decision making is made on a case by case scenario and is based upon an individual’s medical history and current disease diagnostic indicators. Having tools available that could help increase the rationalisation process for choosing a particular course of action at the individual level would not only aid the clinical management of these patients but result in enhanced patient care. Tailored or “personalised medicine” as it is referred to, is receiving considerable interest from the human clinical field. New technologies are becoming increasingly available to the medical arena having highthroughput capabilities to perform rapid bio-profiling of individuals. These molecular fingerprints, or biomarkers as they are more commonly known, provide an extremely powerful mechanism in which to exploit diagnostic and prognostic information regarding disease course and therapeutic outcomes for individual patients. The potential of these technologies to detect individualised molecular fingerprints are not restricted to only human medicine. Biomarker technologies are now being translated into the veterinary arena and offer the same potential to the veterinary practitioner as they do to their counterparts within human clinical medicine – that is the ability to personalise the treatment of individual patients resulting in enhanced patient care to unprecedented levels. Keywords: Biomarker; Proteomic; SELDI; Oncology; Personalised medicine INTRODUCTION Phenotypic signature patterns - biomarkers This paper was commissioned by FECAVA for publication in EJCAP activated is one of the primary mechanisms in which an animal may control its normal physiological function. The products of gene expression (RNA, protein, carbohydrate, lipid etc) can be considered as an organism’s phenotype and the ability to monitor these signature patterns during normal physiological processes would provide a useful mechanism in which to monitor overall functional status [1]. Deviation in the expression of these molecular fingerprints could therefore represent the first sign in the development of a pathological state. The production of diagnostic tools which have the ability to profile The genome represents the total genetic composition of a biological organism and through co-ordinated temporal (time) and spatial (location) gene expression the development of cells and tissues with specialised function occurs. The overall result is the production of an organism with defined attributes and accounts for both species differences and individual breed characteristics. Enabling subsets of genes to be specifically activated and de- (1) Shahid Mian BSc (Hons) Phd., K. Slater BSc (Hons) Phd., PetScreen Ltd, Biocity, Pennyfoot St., Nottingham, GB-NG1 1GF. (2) Correspondence should be addressed to Email: [email protected] (3) Tom Cave BVSc MSc (Clinical Oncology) DSAM MRCVS Cave Referrals, Sandwell, 7 Hector Stones,Woolalvington Somerset GB-TA7 8EG Email: [email protected] 63 Biomarkers and Personalised Medicine Single versus multiple biomarkers a patient’s molecular fingerprint to monitor pathological changes would provide a novel mechanism in which to monitor disease onset and its progression [2]. Phenotypic differences within an individual companion animal are not restricted to species, age, sex, breed, single nucleotide polymorphisms (SNPs) but also within an individual’s metabolic state, disease and immune status etc [8]. While certain expression patterns within an organism are relatively constrained (e.g. proteins associated with the differentiation status of a specialised cell such as a cardiomyocyte) the temporal and spatial pattern of other genes need to be co-ordinately activated, repressed and their gene products modified and turned over in response to meet the daily physiological changes required to maintain homeostasis. Environmental factors can also influence phenotypic expression patterns throughout the life of an animal [9]. A patient therefore represents a mixture of conserved and dynamic subsets of gene expression patterns. How is it possible with such biological heterogeneity therefore to identify biomarkers that will be of clinical relevance? The answer is believed to reside in the use of multiple rather than single biomarkers [10]. Multiple biomarkers represent a composite pattern populated by several key differentiators which indicate the normal versus the pathological state. This approach is expected to achieve the levels of diagnostic redundancy needed for personalised veterinary care. Unless a marker is specifically associated with a diseased state and is not expressed in any other tissue type, it is unlikely that clear demarcation between normal and diseased states will ensue using a simple presence/absence diagnostic tool. Diagnostic assays that can accurately distinguish between the number of true positive cases for a disease indication (sensitivity) and true negative cases (specificity) will be essential if the field of veterinary medicine is to move towards personalised healthcare. Given the nature of genetic variation not only from species to species but from breed to breed, it is likely that multiple biomarkers will be essential to deal with inter and intra group variation. Biomarkers can be described as phenotypic signature patterns of a given physiological state(s). As such, they have the potential to represent a variety of biological processes which may include, for example, normal or diseased conditions. In principle these molecular fingerprints can be elicited from any biomolecule which is expressed from an organism’s genome (e.g. RNA, protein) and by extrapolation therefore, exist within any tissue type implicated to a particular physiological process. Biomarkers are receiving considerable attention by clinical practitioners of human medicine due to their translational application as diagnostic or prognostic indicators [3]. They have been used as phenotypic indicators for early disease detection and progression in a wide range of pathologies extending over several medical disciplines e.g. oncology, renal, cardiac, immunological, neurodegeneration etc [4]. New technologies have arisen to meet this growing demand for rapid biomarker identification. It is envisaged that they will be able to provide greater levels of sensitivity and specificity than is currently afforded by conventional disease markers [5]. An ability to identify biomarker patterns from specific patients with defined pathologies could therefore, offer the promise of a personalised approach to healthcare [6]. There would be many advantages of adopting such a strategy to clinical practice. It could for example facilitate the selection of treatment regimes in which a patient may possess a high probability of responding whilst avoiding therapeutics that are likely to be ineffectual and/or likely to show significant toxicity to non-target tissues [7]. Providing such tools to clinical practitioners would provide a mechanism in which to rationalise the clinical decision making process for a given patient using data derived from diagnostic biomarker patterns. Biomarker identification – the post genome technologies Owners of companion animals and the veterinarians who treat them are now demanding ever increasing standards of quality care administered to pets. Translating biomarker technologies with diagnostic/predictive capability to the veterinary field would provide one such mechanism in which to facilitate this process. The rationale for such a directed approach is simple. Each patient which is presented clinically to a veterinarian will be assessed at an individual level, i.e. on a case by case scenario. Factors such as previous medical history, current clinical manifestations, type of animal, and risk to particular pathologies will then set in motion a series of diagnostic investigations. Integration of all of these factors would facilitate the initiation of a course of clinical action with concomitant patient monitoring for suitable therapeutic response. Such a dynamic situation represents a highly challenging environment for clinical practitioners, especially veterinarians who unlike their clinical counterparts within human medicine, have to deal with a variety of animal species with their predisposition for particular diseases. Biomarkers may offer the potential therefore to identify key disease indicators at the individualised level for a particular species of animal. In 2004 the International Human Genome Sequencing Consortium published a highly accurate sequence annotation of the human genome from approximately 3 billion base pairs of genetic code with 99% sequence coverage [11]. It is believed that the human genome encodes for some 20,000-25,000 genes and taking into consideration such events as alternative splice variants and post-translational modifications there may be somewhere in the order of 500,000 to 1 million gene products in total. In 2003 an initial publication regarding the genomic sequencing of canine was reported [12]. With approximately 2.4 billion base pairs and an estimated 20,000 genes, it is likely that the total number of gene products will be similar to that found in humans. Identifying biomarkers with clinical relevance to the veterinary field will be extremely challenging given not only the number of biological products with biomarker potential for a given animal species with, but also the different separation and isolation characteristics which will be associated with different classes of biomolecule (e.g. RNA, protein, lipid). In order to make the problem tractable, several areas have emerged to analyse each subclass of major molecule in this post-genomic area. For example the study of RNA transcript expression is referred to as transcriptomics [13], while the analysis of 64 S. MIAN, K. SLATER, T.CAVE EJCAP - Vol. 16 - Issue 1 - April 2006 Figure 1: A Time-of-Flight (ToF) mass spectrometer. A laser is fired at the target support containing the clinical sample and the proteins are ablated from the surface (red spot). The molecules are then accelerated in a flight chamber and hit the detector at rates which are inversely proportional to their mass. Figure 2a: Proteomic profiling derived via the mass spectrometric analysis of proteins from a biological sample. The y-axis represents relative intensity value while the x-axis denotes the mass:charge value for each peak. metabolite expression is known as metabolomics [14]. The study of protein expression patterns whether in single cells or complex tissues such as blood plasma, is known as the field of proteomics [15, 16, 17]. While several technologies have been developed to deal with the complex biological diversity of protein populations (e.g. antibody/antigen microarrays; surface plasmon resonance), one approach using mass spectrometry is proving to be an extremely powerful tool in the search for diagnostic biomarkers with clinical relevance [18, 19, 20, 21]. proportional to their mass and as such small molecules arrive at the detector faster than larger molecules. In this manner, a relative intensity spectrum can be produced from a clinical specimen in which intensity is represented on the y-axis and m/z (mass:charge) is denoted on the x-axis (Figure 2a). A simple comparison of two mass spectra e.g. one derived from a serum sample taken from a dog without cancer and one taken from an animal with cancer may enable differences in protein expression patterns to be rapidly identified (Figure 2b). These proteomic based biomarkers may therefore form the basis of a diagnostic test. Different methodologies can be adopted to introduce biological specimens into mass spectrometers for proteomic analysis and one key approach which has received considerable interest is where the biological sample is prepared as a mixture with an energy absorbing molecule called matrix. The biological sample and matrix are co-crystallised on a solid support surface (the process is referred to as MALDI (Matrix Assisted Laser Desorption/Ionisation)) and the mixture analysed by ToF mass spectrometry. The advantage of such an approach Seldi Mass spectrometry is an analytical tool which has the ability to accurately measure the mass of a molecule and the time-offlight instruments (ToF) have been proving to be extremely useful in the search for disease related biomarkers (Figure 1) [22, 23, 24, 25]. Proteins entering the mass spectrometer are ionised and accelerated down a field free flight chamber where they hit a detector. The speed at which molecules “fly” is inversely A Peak X B Figure 2b: A serum biomarker profile taken from a dog with no pathology (A) and a dog with confirmed cancer (B). In Figure 2A peak X is noted to have a higher relative intensity value than the animal with cancer. Figure 2B shows the presence of peak Y which is absent from the animal without disease. Peak Y Mass/Charge 65 Biomarkers and Personalised Medicine clinically is that high throughput automated procedures can facilitate the screening of hundreds to thousands of patient samples in a relatively short time. Identification of potential markers necessitates the use of hundreds of specimens in order to develop statistically confident biomarkers which could form the basis of novel assays. Originally this was extremely difficult as many of the proteomic platforms did not lend themselves immediately to high throughput analysis. However, the drive to identify disease related biomarkers has resulted in the emergence of new technologies with high throughput capability and integrated workflow processes. The result was no longer a constraint on sample processing and data generation, but an ability to process the large volumes of proteomic data which are necessary for the identification of clinical biomarkers. One mechanism to deal with this issue was to implement the use of computer programmes which have an ability to recognise expression patterns associated with particular phenotypes e.g. normal or disease conditions [31, 32]. To date a variety of approaches have been implemented in order to “mine” data for biomarker expression patterns. Data mining, as it is referred to, assists in rapidly identifying the most important protein candidates having diagnostic /prognostic potential. Methodologies such as CART (Classification and Regression Tree analysis), PCA (principal components analysis), and artificial neural networks have been used to assist in biomarker identification [33, 34]. The power of computational analysis for clinical biomarkers lies in the fact that they can analyse literally millions of data points in a relatively short time providing a cohort of proteins which may be useful as predictive indicators. Once key biomarkers have been identified, these algorithms have been utilised to predict the pathological status of additional blind clinical samples with high degrees of accuracy. In MALDI based applications the biological sample is prepared for mass spectrometric analysis prior to deposition on the MALDI target plate through a series of clean-up processes enabling the complexity of the clinical specimen to be reduced and mass spectrometric analysis greatly simplified. An alternative approach is to use a solid support which has a chemically modified surface (e.g. possessing antibody coating for the selection of particular epitopes or having biochemical modifications for the preferential selection of particular classes of proteins/peptides (e.g. hydrophobic, hydrophilic, cationic, anionic etc)). The use of this type of modified solid support or “protein chip” is known as SELDI (Surface Enhanced Laser Desorption/Ionisation) and it has a number of advantages over conventional MALDI. These include both rapid sample clean-up (as it occurs on chip rather than off) and mass spectral reproducibility. As with conventional MALDI, matrix is applied to the protein chip to form a protein crystalline structure and the biological sample is analysed directly using ToF mass spectrometry. The SELDI protein chip technology has been used to characterise biological material from a variety of sources in the search for biomarkers with clinical relevance 26, 27, 28, 29]. Clinical precursor material which has been analysed includes serum, plasma, solid tissue, urine, cerebral spinal fluid etc. The versatility and adaptability of the system makes it highly suitable for clinical applications where the types of biological material being presented for diagnostic analysis are varied and a requirement to process large sample numbers in relatively short time periods is necessitated [30]. As such the potential for developing novel diagnostic tools for veterinary medicine is significant using this type of approach. CLINICAL APPLICATIONS OF SELDI PROTEIN CHIP TECHNOLOGY TOWARDS BIOMARKER IDENTIFICATION Bioinformatics – computer algorithms for biomarker identification In the search for biomarkers with clinical diagnostic/prognostic capability, bottlenecks were originally confined to the lack of reproducible throughput of hundreds of patient samples. Ovarian cancer represents a highly aggressive gynaecological tumour which is normally innocuous to the patient until presentation at late stages. Clinical manifestation is likely to coincide with metastasis and increased biological aggressiveness, making surgical resection and therapeutic intervention extremely difficult. Early detection of ovarian cancer results in high rates of patient cure. The need for diagnostic biomarker assays with greater sensitivity for detecting true positive cases is therefore justified. In 2002 a seminal paper published in the Lancet by Petricoin et al [35] presented data to show how proteomic profiling using SELDI protein chip technology followed by analysis by ToF mass spectrometry could be utilised to produce a “protein fingerprint” of serum. Initial molecular profiling was performed upon 50 patients with ovarian cancer and 50 control individuals who where either disease free or had benign conditions. Using a “supervised” learning algorithm (a computer program in which the user informs the algorithm which profiles are derived from cancer patients and which are not; in this manner the programme has a basis upon which to identify biomarker peaks associated with each diagnostic class “cancer” Squamous cell carcinoma in a cat. 66 S. MIAN, K. SLATER, T.CAVE EJCAP - Vol. 16 - Issue 1 - April 2006 Figure 3: A schematic of how different peaks can be detected using mass spectrometric analysis on SELDI chips using anion exchange chromatography in order to fractionate. The mass:charge value is presented on the x-axis while relative intensity and elution phase are shown on the y-axis. and “non-cancer”) to train an iterative searching program, 116 blind serum sample proteomic profiles (50 cancer and 66 noncancer) were then presented to the trained architecture. From this study 100% of ovarian cancer patients and 95% of noncancer individuals were correctly classified. While flaws were identified in this original study [36] it proved that serum biomarkers could be used as basis for classifying patients diagnostically. Since then, biomarker profiling of serum has been used to discriminate patients with cancer from those without in a number of oncological indications including prostate [37], breast [38], ovarian [5] and lung [39]. as patients who either do or do not progress to stage IV. The potential of identifying at risk individuals for disease progression using biomarkers was shown to be feasible using this technological approach. Biomarker identification using SELDI protein chip technology for disease identification has not been restricted to the use of serum. It has been applied to tissue sections e.g. for grading tumours [41] or identification of biomarkers associated with disease, cell lines for chemo-response [42], urine for biomarkers associated with bladder cancer [43] and cerebral spinal fluid. The potential for human personalised medicine using these types of novel approaches to assess risk of disease onset, its progression and even therapeutic response for individuals is promising. By analogy their implementation into veterinary practice has the potential to aid clinical decision making processes for patients to an equal degree. Mian et al have used a similar profiling methodology in conjunction with supervised training algorithms to classify serum samples taken from melanoma patients with either stage I or stage IV disease [40]. Two hundred and five serum samples from 101 early-stage (American Joint Committee on Cancer [AJCC] stage I) and 104 advanced stage (AJCC stage IV) melanoma patients were profiled using SELDI protein chip technology and linear ToF mass spectrometry. 109 samples (representing approximately equal distribution of both stages) were used as a training set for an artificial neural network (ANN) computer algorithm. ANNs mimic animal brains in that they learn through an iterative process of trial and error. Once training was completed the algorithm was then used to classify 96 blind proteomic profiles derived from the remaining group of stage I and stage IV patients. It was found that 88% of samples were correctly classified. Extending the study further, these authors profiled the serum taken from 55 patients with stage III disease and one year clinical follow-up. 28 patients were known to have progressed to stage IV disease whereas 27 did not. Using biomarker analysis, patterns of expression could be identified by the ANN enabling 80% of the patients to be correctly classified Application of SELDI protein chip to canine cancer serum fingerprinting In order to ascertain the potential of SELDI proteomic profiling for biomarker discovery in veterinary clinical samples, these authors conducted a proof of principle study using serum taken from dogs with a variety of cancers (mast cell/lymphoma) versus dogs without disease. Each serum sample was fractionated initially using anionic exchange chromatography (enriching for proteins which possess negative regions) and eluted with sequential buffers of increasing pH (pH3, pH4, pH7, pH9 and organic). Fractionation of any complex biological sample (tissue/serum etc) is critical if clinically important biomarkers of low concentration are to be detected. It has been widely reported that high abundant molecules e.g. serum albumin, IgG may 67 Biomarkers and Personalised Medicine A Biomarker Intensity B C Mass/charge Figure 4a: Mean intensity values for a highly significant serum biomarker are presented for the cancer and normal populations. Figure 4b: Visualisation of the reduction in relative intensity value for the biomarker between normal and cancerous serum. Figure 4c: A receiver operating characteristic (ROC) plot showing the ability to detect true positives (sensitivity) from false positives (1- specificity). Figure 5: Separation of cancer and normal populations using PCA (principal components analysis) for peaks identified in each of the fractions indicated. Three components have been applied to account for the majority of variation in the proteomic profiles. 68 S. MIAN, K. SLATER, T.CAVE EJCAP - Vol. 16 - Issue 1 - April 2006 mask the detection of disease associated biomarker proteins. The removal of these molecules by reducing sample complexity may therefore facilitate the detection of novel disease related biomarkers which are present in very low amounts. Figure 3 shows how a serum sample can be fractionated into alternative protein components using only a single type of SELDI chromatography (anionic exchange). A comparative analysis between fractionated and un-fractionated serum indicated that a greater number of peaks could be detected in the fractionated serum compared to the non-fractionated sample (321 versus 134 peaks respectively – data not shown). The greater the number of protein peaks detected the higher the probability that one or more may provide the basis of a diagnostic biomarker pattern with disease association. Epitheliotrophic cutaneous T-cell lymphoma (mycosis fungoides) in a dog. In order to identify peaks having potential utility as biomarkers for cancer, statistical analysis using t-testing was performed to select candidates which had significant differences (P<0.05 level) between normal and cancer patient serum samples. Initial data passing revealed that 81 peaks had statistically significant pvalues at the P<0.05 level (data not shown). An example of one of the significant peaks is presented in Figure 4. A scatter plot of intensity values for the biomarker in both normal and cancer associated serum samples is provided in Figure 4a. This peak is significantly down-regulated in cancer serum samples (P<0.001) compared to non-diseased animals. Figure 4b shows the biomarker which has been identified via automated peak detection software. Figure 4c presents data in the form of a ROC (Receiver Operating Characteristic) curve which produces a measure of the ability of a biomarker to discriminate between true positives i.e. cancer patients (also referred to as sensitivity) and false positive i.e. negative patients which are classified as positive (this is calculated as 1-specificity). The AUC (Area Under the Curve) value was calculated to be 0.99 indicating good demarcation of this biomarker peak to identify true positives from false positives within the cohort of samples tested. As biological variation increases e.g. breed, sex, tumour type then it is likely that single markers which show extremely good promise within the early stages of diagnostic evaluation do not have sufficient power to deal with the complexity seen clinically. identification are far reaching and include the possibility of choosing the most appropriate form of therapy for a given individual, developing novel therapeutics and ultimately understanding the cause of disease onset and progression. CONCLUSIONS Human clinical medicine is moving towards the exploitation of genetic information via post-genome technologies. Biomarker assays represent one key evolutionary product from this era. Veterinary medicine is also capitalising upon these advances as the profession moves rapidly to exploit post-genome information and facilitate its translation into a clinical setting. The results for companion animal practice both in the short and medium/longterm will be the production of significantly improved diagnostic assays for a wide range of clinical pathologies. Additionally, it should facilitate production of novel therapeutics with greater specificity and less toxicity. This will ultimately translate to a more directed approach to patient care than can be afforded with current veterinary medical practice and aid veterinarians in their decision making processes. Additional data analysis using principal components analysis (PCA) (a statistical approach to identify principal components which can account for as much of the variation in data between the two populations) is presented for each of the fractions (Figure 5). 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[43] ZHANG (Y.F.), WU (D.L.), GUAN (M.), LIU (W.W.), WU (Z.), CHEN (Y.M.), ZHANG (W.Z.), LU (Y.) - “Tree analysis of mass spectral urine profiles discriminates transitional cell carcinoma of the bladder from noncancer patient.” Clin Biochem., 2004 Sep;37(9):772-9. REPRINT PAPER (D) M andibulectomy and maxillectomy as a treatment for bone invasive oral neoplasia in the dog – a retrospective analysis of 31 patients Martin Kessler (1) S U M M A R Y From 1999 to 2001, 31 dogs with bone invasive tumours of the jaws were treated by maxillectomy or mandibulectomy at the Hofheim Small Animal Clinic (Germany). In addition to surgery, 3 dogs received chemotherapy, two due to metastatic spread and one after marginal resection of an extensive tumour. The goal of this study was to describe epidemiology and pathology of the various tumours, review the rate of postoperative complications and determine postoperative jaw function with regard to food and water uptake and grasping of sticks or balls. Patient survival times were evaluated and compared to published data. Medium and large sized dogs were overrepresented in this study; the average age was 9.9 years, 20 (65%) of the animals were male and 11 (35%) were female. Of the 31 tumours, 23 (74%) were malignant, 8 (26%) were benign; 21 (68%) were located in the mandible, 10 (32%) in the maxilla. The histologic diagnoses were as follows: squamous cell carcinoma (n = 10, 32%), malignant melanoma (n = 8, 26%), acanthomatous epulides (n = 7; 23%), fibrosarcoma (n = 3; 10%) and one each of osteosarcoma, atypical histiocytoma and central ameloblastoma. Only one dog suffered major postoperative complications resulting in euthanasia. Follow up was available for 23 patients using an owner questionnaire to evaluate function of the jaws after resection. One dog experienced problems that were felt to result in a significant reduction in quality of life. Three other patients had difficulties grasping hard objects but had no problems with food or water uptake. In the remaining dogs no significant functional deficits were reported by the owners. Functional deficits were not associated with the extent or location of jaw resection. Survival times were available from 26 patients, of these 18 were still alive with an average survival time of 14 months. Maxillectomy or mandibulectomy is an appropriate method for treatment of bone invasive tumours of the jaws and has a low complication rate. In most cases postoperative function of the jaws is undisturbed. INTRODUCTION This paper was originally published in: Kleintierpraxis* (2003) 48(5), p.289-300 In small animals the oral mucosa is a frequent primary location for the development of neoplasia. The most common canine tumours of the oral cavity, listed in decreasing frequency are malignant melanoma, squamous-cell carcinoma, and fibrosarcoma. Epulides are the most relevant benign neoplasia of the oral cavity (TODOROFF und BRODEY, 1979; KESSLER und V. BOMHARD, 1997; HORSTIG et al., 1998). Oral tumours have a tendency to invade the surrounding bone, which explains the inevitable and quick recurrence when they are locally excised without the removal of adjacent bone (TODOROFF und BRODEY, 1979). (1) Hofheim Small Animal Clinic, Im Langgewann 9, D-65719 Hofheim E-Mail :[email protected] * Presented by DGK-DVG (Germany) 73 Mandibulectomy and maxillectomy as a treatment Maxillectomy or mandibulectomy have been described in the literature as therapy of invasive oral tumours with good long term results (TODOROFF und BRODEY, 1979; BRADLEYet al., 1984; KOSOVSKY et al., 1991; SCHWARZ et al., 1991a and b; WALLACE et al., 1992). Until now in the German literature, only a few case reports have been published. This publication describes the most common bone invasive canine oral tumours and retrospectively examines clinical results of 31 patients undergoing maxillectomy or mandibulectomy due to such tumours. Statistical evaluation was performed for the most important types of tumours and their locations, type and extent of maxillectomy or mandibulectomy, postoperative complications and the patients’ survival times. With the aid of an owner’s questionnaire, postoperative jaw function such as biting ability and food and water uptake was examined. Oral Malignant Melanoma (Fig. 1) Oral melanomas occur more frequently in dachshunds, cocker spaniels and poodles. In one study, these three breeds alone accounted for almost 50% of patients with oral malignant melanoma (KESSLER, 1999). Although the tumour is usually partly or completely pigmented, occurrences of ‘amelanotic (pigmentless) melanoma’ in the oral cavity are not uncommon. Melanomas are characterised by their aggressive biologic behaviour leading to both local infiltration and swift metastatic spread. Metastases are rarely present at the time of diagnosis, however they develop in the majority of patients mainly in the lymph nodes and lungs during the course of the disease. The time between diagnosis and metastatic spread differs greatly between individuals. Even with obvious macrometastases, it has been reported that the survival rate can be up to two years (HAHN et al., 1994). Fig. 2: Squamous-cell carcinoma of the gingiva in a 4 year old mixed breed dog (patient number 10). The maxillectomy extended from the left canine to and including Pm3 (compare Fig. 9). Squamous-Cell Carcinoma of the gingiva (Fig. 2) Oral squamous-cell carcinomas are light red, often ulcerated growths that at an early stage could be misdiagnosed as gingivitis. The surrounding bone is inevitably infiltrated, leading to osteolysis resulting in the loosening or falling out of the adjacent teeth. This type of tumour seldom metastasises, if so then very late in the course of the disease. If metastasis does occur the lymph nodes are most often affected and only seldomly the lungs or other organs (TODOROFF und BRODEY, 1979; SCHWARZ et al., 1991a). The prognosis is good when, through radical treatment, complete resection of the tumour is achieved. Oral Fibrosarcoma (Fig. 3) Oral fibrosarcomas can affect dogs at any age but large and middle sized dogs are predisposed (KESSLER und BOMHARD, 1997; KESSLER, 1999). This tumour occurs most often in the mucosa of the gums and on the hard palate. These tumours have a hard consistency and are contiguous with the surrounding tissue. They are extremely invasive and therefore a macroscopic differentiation between diseased and healthy tissue is not possible. Invasion of the surrounding bone is imminent, as seen in most cases through the presence of osteolysis. The rate of metastatic spread is about 30%. Acanthomatous epulides (Fig. 4) Epulides comprise ca. 30% of all canine oral neoplasia and are the most common benign tumours of the canine oral cavity. The term epulides is only a descriptive clinical expression. Nomenclature and classification varies greatly in the literature. Most often 3 types are distinguished: (1) fibromatous epulides Fig. 1: Malignant melanoma in the maxilla of a mixed breed dog (patient number 18). The ensuing maxillectomy of the right side included Pm1 and extended to just rostral of M3. 74 MARTIN KESSLER EJCAP - Vol. 16 - Issue 1 - April 2006 Fig. 4: Acanthomatous epulis of the mandible in a Belgian shepherd (Patient number 27). A mandibulectomy including Pm3 to M1 was performed. Fig. 3: Fibrosarcoma of the maxilla located around the canine of a 6 year old Labrador Retriever (patient number 20). A maxillectomy was performed from I1 to Pm2 spanning the midline of the hard palate and continuing to the contralateral side. Fig. 5: Ameloblastoma of the mandible in a Swiss Mountain dog (patient number 30). A bilateral rostral mandibulectomy was performed from and including the left Pm3 to the right Pm2. (or E. fibropapillomatosa); (2) ossifying epulides; (3) acanthomatous epulides. The last group has been more recently termed “peripheral” or “acanthomatous ameloblastoma” and in publications from the UK as “basal cell carcinoma”. This type is characterised by quick and invasive growth. Invasion and destruction of the surrounding jaw bone is evident in most cases, resulting in the impression, both clinically and radiographically, of a malignant tumour. Metastatic spread however does not occur. The authors have found that acanthomatous epulides make up about 20% of all epulides (KESSLER and v. BOMHARD, 1997). Medium and large sized dogs are more often affected. predilection. The tumour is locally destructive, as seen radiographically through the presence of osteolysis, however does not metastasise. MATERIALS AND METHODS This study retrospectively examined 31 dogs of different breeds presented with oral bone invasive tumours at the Hofheim Small Animal Clinic from 1999 to 2001. Before surgery, every patient underwent a complete diagnostic workup including a histopathological biopsy. The extent of invasiveness into the surrounding bone was determined with the help of computed tomography (CT). Radiography of the thorax was performed in every patient with a malignant tumour to determine the presence or absence of metastases. Ameloblastoma (Fig. 5) Ameloblastoma, also referred to as adamantinoma, belongs to the family of tumours originating from the dental lamina (‘odontogenic tumour’) and is the least differentiated, non inductive tumour in this group. Different schools of thought exist on the differentiation between (‘central’) ameloblastomas originating in bone and acanthomatous epulides (‘peripheral ameloblastoma’) (VERSTRAETE et al., 1992). The ameloblastoma is the most common odontogenic tumour and has been described in dogs ranging in age from 3 to 13 years. This tumour can arise from any part of the gingival with no specific site Chemotherapy was performed postoperatively on four patients. Three of the four were diagnosed with a squamous-cell carcinoma (two of these with metastases, one with very extensive growth), and the fourth patient was diagnosed with a metastasised malignant melanoma. The two patients with metastasised squamous-cell carcinoma were treated with an 75 Mandibulectomy and maxillectomy as a treatment mandibulectomy in 6 cases and a partial or complete lateral mandibulectomy in 14 cases was performed. In one case a resection of 75% of the mandible was necessary. Of the maxillary tumours, 3 were removed by a rostral and 7 by a lateral maxillectomy. Administration protocol for cisplatin 1. Diuresis with 0.9 % NaCl, 18 ml/kg/h for 6 h 2. Odansetron (Zofran®) 2-4 mg/dog per os 3 h after beginning diuresis 3. Cisplatin (55-60 mg/m2 BSA) as continuous intravenous drip infusion over 20 minutes 4. Diuresis with 0.9 % NaCl, 18 ml/kg/h for 2 h Three patients suffered complications directly after completion of the surgery. After rostral mandibulectomy (from and including the right M1 to the left PM2), one patient (Table 3 No. 13) experienced the temporary presence of a ranula, which spontaneously disappeared after two weeks. In two patients healing of the surgical wound was compromised due to dehiscence with infection. The first patient (Table 3, No. 18; resection PM1 to M3 reaching past the midline) suffered dehiscence after a caudal maxillectomy, which was successfully repaired by revision surgery. The second patient (Table 2 No. 4) also experienced dehiscence after a caudal mandibulectomy (complete mandible caudal from PM2). After a revision, dehiscence occurred again, which led the owner to opt for euthanasia. Administration protocol for Carboplatin 1. Odansetron (Zofran®) 2-4 mg/dog i.v. just before beginning chemotherapy 2 2. Carboplatin 290-300 mg/m BSA over 20 minutes i.v. Table 1: Administration protocol for Platinum derivatives alternating application of cisplatin or carboplatin (treatment and dosage see Table 1) with bleomycin (12000 IU/m2 body surface area (BSA) s.c. every 2 weeks after the platin application). Patient number 8 with the aforementioned extensive squamous cell carcinoma of the maxilla was treated with a cisplatin monotherapy (5 applications of 55-60 mg/m2 BSA i.v. every four weeks). The treatment of the dog with the metastasised malignant melanoma consisted of a combination preparation of Carboplatin (290 mg/m2 BSA over 20 min i.v.) and human interferon (interferon-a 2a – Roferon-A “, Roche; 3 million IU/m2 BSA s.c. weekly for 3 months). In the cases of 23 patients, information could be obtained from the owners about water and food uptake, as well as the ability of the dogs to fetch sticks or balls. Of the remaining 8 patients, owners of seven could not be contacted, and in one dog, as already mentioned, euthanasia had been performed due to recurring suture breakdown. From evaluation of the 23 dogs, only one (Tab. 3, No. 12, partial mandibulectomy PM4-M1) was reported by the owner to experience a handicap that reduced quality of life. This patient experienced problems with food uptake and therefore had to be hand fed. The owner stated that the ‘lower jaw repeatedly caught on the canines’. Three patients (mandibulectomies No. 3 and 13, maxillectomy No. 29) did not have problems with food uptake, but had difficulties taking hard objects between the jaws (chew-bones, sticks, balls). Patient Patient follow up occurred either through a physical examination at the clinic or telephone conversation with the owner. Special emphasis was placed on judging the ability of the patient to eat or drink and to play with balls or sticks. RESULTS (TABLES 2 TO 5) Of the 31 bone invasive tumours of the jaws included in this study, 23 (74%) were malignant; 8 (26%) were diagnosed as benign by histopathological examination. A total of 21 tumours (68%) were located in the mandible, 10 (32%) in the maxilla. The following tumours occurred in decreasing frequency: squamouscell carcinoma (n=10, 32%), malignant melanoma (n=8, 26%), acanthomatous epulides (n=7, 23%), and fibrosarcoma (n=3, 10%). One each of the following tumours occurred: osteosarcoma, atypical histiocytoma and ameloblastoma. Male dogs were more often affected: in this study 20 (65%) of the patients were male (entire or castrated), whereas only 11 (35%) were female (entire or spayed). The average age of the patients was 9.9 years (range 4-16 years). Dogs of different breeds as well as mixed dogs were affected, however most of the patients were middle to large breeds. Breed predispositions could not be determined due to the small number of cases included in the study. The extent of jaw resection was determined by location and size of the affected area. Additional computed tomographic examination was performed for tumours of the maxilla to optimise the planning of the operation (Fig. 6). Bone was removed either with an oscillating saw and/or an osteotome and mallet. Of the cases with a tumour of the mandible, a rostral Fig. 6: CT used in the surgical planning of a maxillectomy to remove an extensive squamous cell carcinoma located far caudal in the oral cavity (patient number 8). Notice the almost complete osteolysis of the right maxillary bone and parts of the zygomatic arch. CT is essential for the planning and preparation of this type of surgery. 76 MARTIN KESSLER No Description 1 2 3 Retriever, 7y, fn Small Munsterland dog; 12y, m Spitz-mix 14y, m EJCAP - Vol. 16 - Issue 1 - April 2006 Mn /Mx Mn Mn ST (mo) 18 L canine – R PM2 R PM1-M3 outcome alive Fu/Wu/St/Ba no further contact German Shepherd 9y, mn Mn Mixed breed, medium 11y, m Ballonaise 13y, mn Mn Mn R M1-L PM4 17 alive no problems 7 Fox Terrier mix 12y, fn Mn PM2-joint 13 alive no problems 8 German Shepherd mix 10y, f 5 6 comments no problems complete mandible from PM1 caudally complete mandible from L PM2 caudally L PM3-M2 4 Mn resection 21 alive not possible to chew bones, jaw “crooked” 0,5 Eutha 19 alive no problems Dehiscence Lnn metastasis, Chemo: 4xCarbo + 4x Bleomycin 4 mo post OP: Lnn. followed by resection and Chemo: 6x both Cisplatin and Bleomycin Chemotherapy: 5xcisplatin Mx R PM3-M3, 11 alive no problems zygomatic arch, lateral maxillary bone 9 Airedale Terrier Mx L PM3-M1, 24 alive no problems 8y, fn 1/3 of hard palate 10 Bernese Mountain Mx L canine15 alive no problems dog - Mix 4y, m PM3, over palatine midline y= age in years - Mn=mandible - Mx=maxilla – fn=female neutered – mn=male neutered – m=male – f=female - Resection: start of segment including tooth mentioned – L=left – R=right - complete=including Ramus of mandible – ST=survival time – Fu/Wu= food-/water uptake – St/Ba – playing with stick or ball - Eutha = euthanasia Table 2: Squamous-cell carcinoma of the jaw Significant side effects did not occur. Patients with malignant melanoma experienced the worst survival rates (Table 3). Of the 7 patients whose information was available, only two were still alive (survival time 7 and 9 months postoperatively) at the time of original publication in 2003. Five patients required euthanasia due to recurrence (2 patients) and recurrence and metastasis (3 patients) of the tumour. The survival times were 2, 3.5, 6, 6 and 16 months respectively. The patient (Tabl. 3, number 12) with lymph node metastasis at the time of the operation was treated postoperatively with a chemoimmunotherapy and had the longest survival time of all melanoma patients (16 months). As above, no significant side effects occurred as a result of the chemotherapy. Survival times could be determined for 3 of the 4 patients with oral sarcomas (Tabl. 4). One patient died 7 months after surgery due to illness not associated with neoplasia and without evidence of recurrence. The remaining two patients with sarcoma were still living in 2003 without tumour recurrence (6 and 20 months). Of the eight patients with acanthomatous epulides, information number 13 was always wet in the ventral neck due to salivation. The remaining 19 patients were not reported by the owners to experience any type of difficulties. Of the 31 patients, information on the survival times of 26 patients could be gathered. Eighteen were still alive at the time of this manuscript’s original publication in 2003 with an average survival rate of 14 months (compare tables 2 to 5). Of the 10 patients with squamous-cell carcinomas, as stated above, euthanasia was performed in one due to repeated suture dehiscence and one other patient was not available for follow up. The remaining 8 patients were still alive at the original publication in 2003, with a remission time of 11-24 months (average 17.25 months, table 2). All 3 patients treated postoperatively with chemotherapy were still alive in 2003: two patients with metastasis (patients 6 and 7) lived without further spread for 13 and 17 months, respectively, and one patient (number 8) with a large affected area of the maxilla has lived 11 months without signs of tumour recurrence (Fig. 7). 77 Mandibulectomy and maxillectomy as a treatment No Description 11 Spitz mix 13y, fn 12 Yorkshire Terrier mix 10y, m Mn/Mx Mn resection R PM4-M2 ST (mo) 6 Outcome Eutha Fu/Wu/St/Ba no problems Mn L PM4-M1 16 Eutha 7 alive difficulty Fu; St/Ba impossible; jaw “catches on canines” difficulty eating large pieces, drooling 13 Dachshund 12y, f Mn R M1- L PM2 14 Poodle mix, 14y, m Bearded Collie; 10y, m Poodle 13y, m Mix-breed 14y, m Mn Mx bilateral rostral to PM1 L PM2-M3 9 alive no problems Mx R canine – L I3 2 Eutha no problems 15 16 17 comments recurrence and metastasis LN mets, Chemo: 6x Carbo & Interferon temporary ranula no further contact tumour recurrence Mx Size of an egg, 6 Eutha no problems tumour extending to recurrence soft palate 18 Small mixed Mx R PM1-M3 3.5 Eutha no problems dehiscence, 2nd breed extending OP; tumour 12y, fn across midline recurrence & mets y= age in years - Mn=mandible - Mx=maxilla – fn=female neutered – mn=male neutered – m=male – f=female - Resection: start of segment including tooth mentioned – L=left – R=right - complete=including Ramus mandibulae – ST=survival time – Fu/Wu= food-/water uptake – St/Ba – playing with stick or ball - Eutha = euthanasia Table 3: Malignant melanoma of the canine jaw about the survival times is available from 7 (Tabl. 5). One of the 7 dogs required euthanasia 12 months postoperatively not caused by tumour associated illness. The remaining patients were still alive in 2003 with a remission time of 3 to 35 months (average 15.5). KESSLER and v. BOMHARD, 1997). In this study, 21 patients were affected with tumours of the mandible compared to only 10 of the maxilla. Reported in the literature is a disproportionately higher incidence of squamous-cell carcinoma (TODOROFF und BRODEY, 1979) and acanthomatous epulides (WHITE, et al., 1985) in the mandible compared to in the maxilla. DISCUSSION Partial Maxillectomy/Partial Mandibulectomy A mandibulectomy or maxillectomy is performed to resect a malignant jaw tumour or a bone invasive benign neoplasm (BERG, 1998). Conservative ‘excisions’ of the tumours, such as Epidemiology In this study, the tumours malignant melanoma, squamous-cell carcinoma, fibrosarcoma, and acanthomatous epulis were identified as the most common bone invasive tumours occurring in dogs, confirming results observed in other publications (TODOROFF and BRODEY, 1979; KESSLER and v. BOMHARD, 1997; HORSTIG et al., 1998). The age and breed range were similar to those in other publications, older dogs being more often affected (COHEN et al., 1964; TODOROFF and BRODEY, 1979; EVANS and SHOFER, 1988; WALLACE et al., 1992). According to other studies oral sarcomas also affect younger individuals (COHEN et al., 1964; TODOROFF and BRODEY, 1979). However, statistically this could not be supported in this study due to the small number of cases. For the same reason, determining breed disposition was also impossible, however middle and larger breed dogs seem to make up the majority of affected individuals, as is the case in this and other studies (TODOROFF und BRODEY, 1979; SCHWARZ et al., 1991a; Fig. 7: Cosmetic result after extensive maxillectomy 11 months after surgery (Patient number 8, see also Fig. 6). Jaw function is completely preserved. 78 MARTIN KESSLER Tumour histology FS Mn/MX resection Mn R PM4-joint Labrador Retriever 6y, fn. FS Mx Fox Terrier 9y, f Mixed breed 12y, m FS Mx OS Mn L I1-PM2 2/3 width of palatine R PM1 – L PM2 both rostral to PM1 No Description 19 German shepherd, 20 21 22 EJCAP - Vol. 16 - Issue 1 - April 2006 ST (mo) 20 outcome alive comments no further contact no problems no further contact 6 alive no problems y= age in years - Mn=mandible - Mx=maxilla – fn=female neutered – mn=male neutered – m=male – f=female – FS=fibrosarcoma – OS=osteosarcoma - Resection: start of segment including tooth mentioned – L=left – R=right – ST=survival time – Fu/Wu= food-/water uptake – St/Ba – playing with stick or ball Table 4: Sarcomas of the canine jaw local removal or scraping, leads almost inevitably to a swift recurrence (TODOROFF und BRODEY, 1979; HARVEY et al., 1981; SCHWARZ et al., 1991a and b). The resection involves the removal of the affected jaw segment including the teeth. When performing a mandibulectomy, it is not necessary to stabilise or connect the remaining jaw segments (WITHROW and HOLBERG 1981). The reconstruction is achieved by suturing the lingual and labial mucosa as well as their anchoring to the remaining segment(s) of the lower jaw (Fig. 8a and b). During mandibulectomy, special care must be taken to avoid damaging the nerves of the tongue or excretory ducts of the sublingual salivary glands. The operation is more demanding the further caudal the mandibulectomy. When performing disarticulation of the temporomandibular joint, care must be taken not to injure the mandibular alveolar artery, vein and lingual nerve, which run directly medial to this joint. Resection of the maxilla requires the closure of the ensuing oronasal defect. This can be accomplished by elevating a buccal mucosal flap originating from the adjacent upper lip (Fig. 9). A maxillectomy is also invariably more difficult with increasing amount of bone/tissue removal or the further caudal the tumour is located or resected. The most demanding resections are those requiring either a complete reconstruction of the tempero-mandibular joint region or incorporating the rostral soft palate. Depending on the type of tumour, a certain amount of invasive growth is expected and should be considered when planning the resection. The tumour mass, determined using CT and gross appearance, as well as a safety margin of normal soft tissue and bone should be excised. For this reason it is imperative to determine the tumour type. In addition to determining the invasive growth of the tumour (radiographs, CT) and the metastatic spread (fine needle aspirate or biopsy of the regional lymph nodes, thoracic radiographs), a biopsy of the tumour itself using fine needle aspirates or a bone punch is necessary to plan the surgery correctly. According to the experience of the author, the following sufficient distances for the safety margin around the mass should be observed: gingival squamous cell carcinoma approx. 1 cm, malignant melanoma 2 cm, and fibrosarcoma 3 cm (Fig. 10). Acanthomatous epulides can be resected with a safety margin of 0,5-1 cm. Partial maxillectomy or partial mandibulectomy show good cosmetic and functional results (FOX et al., 1997). Also in this study, even after extensive resection, only one patient experienced difficulty with food uptake. Most dogs retained the ability to take unwieldy or hard objects (chew-bones, balls, sticks) between the jaws. In all, 22 of the 23 owners were satisfied with the functional results of the jaw resection. COMPLICATIONS The most common complications after maxillectomy or mandibulectomy are dehiscence, wound infection, disturbance of the salivary gland ducts, difficulty with food uptake, pain, tongue dysfunction and abnormal salivation (WHITE, 1987; MATTHIESEN and MARRETTA, 1990; SCHWARZ et al., 1991a and b; MUIR and ROSIN, 1995). Complications also occurred in this study, however, the overall rate was low. The results were not satisfactory with two patients: euthanasia of one patient due to repeated dehiscence, and food uptake problems of another patient. Both patients with fatal complications underwent extensive resection of the caudal jaw segment. Caudal tumours, as stated also in the literature, are known to have a poor prognosis due to the limited surgical possibilities (SCHWARZ et al., 1991a). Biological behaviour, Therapy and Prognosis The results of this study support what has previously been published about the biological behaviour of oral tumours. Two of the ten patients with squamous-cell carcinoma exhibited metastasis to the mandibular lymph nodes, whereas lung metastases were not evident. In published literature 8 out of 58 animals had lymph node metastases (EVANS and SHOFER, 1998; SCHWARZ et al., 1991a and b; MILLER et al., 1994) and only 1 of 35 dogs had pulmonary metastases (TODOROFF and BRODEY, 1979). Apparently this tumour metastasises at an advanced stage of the disease. At post mortem examination of 11 dogs, metastasis was evident in the lymph nodes of 5 animals and in the organs of 4 animals (TODOROFF and BRODEY, 79 Mandibulectomy and maxillectomy as a treatment Fig. 9: Closure of the resection defect resulting from maxillectomy with a mucosal flap from the upper lip (patient number 10). The pre-operative appearance is shown in figure 2. Fig. 8: Hemimandibulectomy due to fibrosarcoma of the lower jaw (a) post-operative and (b) the resected jaw segment. During soft tissue reconstruction, care is taken to protect the excretory ducts of the sublingual salivary glands Fig. 10: Mandibulectomy due to fibrosarcoma. Because of the severe invasive growth of this tumour, the aim is to excise an additional 3 cm of healthy tissue around the mass. 1979). It can be inferred that this tumour most likely initially metastasises to the lymph nodes, necessitating their histological examination. According to literature reports, squamous-cell carcinomas that develop caudally in the oral cavity have a poorer prognosis. This may be due to the occult growth of this tumour, which causes the animal to be presented for examination at an already advanced stage of the disease. Neither a stronger tendency to metastasise nor an inherent malignant biological behaviour of the caudally located gingival squamous-cell carcinoma has been proven. in veterinary medicine. The authors applied a protocol derived from those in human medicine using a platinum derivative (Cisplatin or Carboplatin) combined in 2 cases with the antitumour antibiotic Bleomycin. The effectiveness of both platinum derivatives is similar, however the method of administration and the costs involved differ. Carboplatin is a newer generation of platinum derivative that is not nephrotoxic and as a result can be administered intravenously over a short time period without diuresis. However, the cost of carboplatin is much higher than that of cisplatin, which makes it economically challenging for Few cases of concurrent chemotherapy in the treatment of metastasised oral tumours or of those with a high metastasis rate are described in the literature. Chemotherapy to treat gingival squamous-cell carcinoma has not yet been established 80 MARTIN KESSLER No 23 24 25 26 27 28 29 30 Description large mixed breed, 10y, m Collie, 9y, f Beagle Crossbred 16y, m Retriever 6y, m Belg. SH 11y, m West Highl. Terrier 9y, f Schnauzer 8y, m Swiss Mountain dog 8y, m EJCAP - Vol. 16 - Issue 1 - April 2006 Tumour histology AE ST outcome Fu/Wu/St/Ba (mo) 3 Mn AE Mn L complete - R Canine R I3 - Canine alive no problems 5 alive no problems AE Mn R I1 - PM1 20 alive no problems AE Mn R I1 - Canine 24 alive no problems AE Mn R PM3 - M1 12 no problems AE Mn R PM1 - M1 35 Eutha (not tumour associated) alive AE Mx L PM2 – R Canine 6 alive AM Mn L PM3 – R PM2 20 alive no problems but no bones or balls no problems Mn/MX resection no problems y= age in years - Mn=mandible - Mx=maxilla – fn=female neutered – mn=male neutered – m=male – f=female – AE=acanthomatous epulis – AM=ameloblastoma - Resection: start of segment including tooth mentioned – L=left – R=right - complete=including Ramus mandibulae – ST=survival time – Fu/Wu= food-/water uptake – St/Ba – playing with stick or ball – Eutha = euthanasia Table 5: Acanthomatous epulides/ ameloblastoma of the canine jaw use in larger animals. When treating with cisplatin, an extensive diuresis protocol is necessary to prevent kidney damage (Table 1). The main side effect of both medications is emesis during application through a direct stimulation of the chemoreceptor trigger zone in the brain. To prevent emesis, odansetron (Zofran®, 4-8 mg/animal p.o.) combined with metoclopramide (0.2 mg/kg i.v.) should be given approximately 2 hours before initiating chemotherapy. Bleomycin does not yet have many applications in veterinary medicine. In this case, Bleomycin was given subcutaneously twice a week. Side effects are rare, but the development of pulmonary fibrosis and a hypersensitivity reaction have been reported, and in individual cases the development of paw pad ulcers occurred. No side effects were observed in the patients in this study undergoing treatment. The survival times of dogs with squamous-cell carcinoma with concurrent chemotherapy are encouraging. Both animals (patients 6 and 7) with extensive metastasis to the lymph nodes survived postoperatively 13 and 17 months, respectively. Patient number 8, who was additionally treated with cisplatin because of the size of the lesion, was still in remission at the time of publication, 11 months postoperatively. difficult to interpret. Even so, in this study the one patient who was treated additionally with chemotherapy and immunotherapy (patient 12) had the best survival time of 16 months. One explanation for the variable survival times of malignant melanomas could lie in their immunogenetic properties, in which the presence of the tumour causes an immunological response. The course of the disease is for this reason dependent on the effectiveness of the patient’s immune system. This property of melanomas can be exploited therapeutically. Various studies involving different immune modulators have been published, for example C. Parvum (MacEWEN et al., 1986), L-MTP-PE (MacEwen et al., 1994), Interleukin, and tumour necrosis factor (MOORE et al., 1991). The authors used human recombinant interferon-α 2a (Roferon-A“, Roche), which was given twice weekly subcutaneously by the owner at a dose of 3 Mio. IU/m2 BSA. This dosage results in serum values of a therapeutic value, however it is known that some patients build neutralising antibodies against the human interferon. Further studies are necessary to determine recommended clinical uses of immunotherapy. The recent introduction of a feline recombinant interferon opens new possibilities in veterinary medicine, however until now no publication has provided data on the best melanoma tumour immunotherapy. Similar to reports in the literature, patients in this study with oral melanoma suffered the shortest survival times. Of over 200 patients reported in the literature undergoing mandibulectomy or maxillectomy, there was a mean survival time of 7.5 to 9 months. However, it is striking that the survival time for oral melanoma varies greatly (1-46 months) (HARVEY et al., 1981; MacEWEN et al., 1986; KOSOVSKY et al., 1991; SCHWARZ et al., 1991a and b). Because of the high rate of metastasis, it seems wise to augment the surgical treatment of malignant melanomas systemically. However, due to the wide range in survival time a comparative study evaluating concurrent therapies would be Oral fibrosarcomas affect both the lower and upper jaw with almost equal incidence and are characterised by local invasive growth into surrounding tissue. The rate of metastasis is lower compared to other oral tumours but higher compared to fibrosarcomas occurring elsewhere. Tumours localised to the maxilla or hard palate have the worst prognosis due to operative restrictions. Even after radical resection, fibrosarcomas have the highest recurrence rate of all oral tumours (SCHWARZ et al., 81 Mandibulectomy and maxillectomy as a treatment BRADLEY (R.L.), (D.P.) SPONENBERG AND (R.A.) MARTIN (1986): - Oral neoplasia in 15 dogs and 4 cats. Sm. Anim. Vet. Med. Surg. 1, 33–42. BURACCO (P.), (A.) BONIOLI, (G.) ROMANELLI et al. 1994: Surgery / chemotherapy in 43 canine and feline oral tumours. Proc. 14th Ann. Conf. Vet. Canc. Soc. 51–52. COHEN (D.), (R.S.) BRODEY AND (S.M.) CHEN (1964): Epidemiologic aspects of oral and pharyngeal neoplasms of the dog. Am. J. Vet. Res. 25, 1776–1779. DUBIELZIG (R.R.) AND (D.E.) THRALL (1982): - Ameloblastoma and keratinizing ameloblastoma in dogs. Vet. Pathol. 19, 596–607. EVANS (S.M.) AND (F.) SHOFER (1988): Canine oral nontonsillar squamous cell carcinoma: prognostic factors for recurrence and survival following orthovoltage radiation therapy. Vet. Radiol. 29, 133–137. FOX (L.E.), GEOGHEGAN, (S.L.), (L.H.) DAVIS et al. (1997): Owner satisfaction with partial mandibulectomy or maxillectomy for treatment of oral tumours in 27 dogs. J. Am. Anim. Hosp. Assoc. 33, 25-31. GARDNER (D.G.) AND (D.C.) BAKER (1993): - The relationship of canine acanthomatous epulis to ameloblastoma. J. Comp. Path. 108, 47–55. GARDNER (D.G.) (1996): - Epulides in the dog: a review. J. Oral Pathol. Med. 25, 32-37. HAHN (K.A.), (D.B.) DENICOLA, (R.C.) RICHARDSON et al. (1994): - Canine oral malignant melanoma: prognostic utility of an alternative staging system. J. Sm. Anim. Pract. 35, 251–256. HARVEY (H.J.), (E.G.) MACEWEN, (D.) BRAUN et al. (1981): Prognostic criteria for dogs with oral melanoma. J. Am. Vet. Med. Assoc. 178, 580–582. HORSTING (N.), (A.) VON REISWITZ, (P.) WOHLSEIN et al. (1998): - Oropharyngeale Tumoren des Hundes - Eine klinische Studie über 79 Fälle. Berl. Münch. Tierärztl. Wschr. 111, 242–247. KESSLER (M.) AND (D.) VON BOMHARD (1997): Tumoren der Maulhöhle beim Hund: Epidemiologische Untersuchungen bei 491 Fällen. In: Kessler, M. (Hrsg.): Kleintieronkologie, Paul Parey, Berlin 1999; 278. KOSOVSKY (J.K.), (D.T.) MATTHIESEN, (S.M.) MARRETTA et al. (1991): - Results of partial mandibulectomy for the treatment of oral tumours in 142 dogs. Vet. Surg. 20, 397–401. LAMONT (E.B.) AND (E.E.) VOKES (2001): Chemotherapy in the management of squamous-cell carcinomas of the head and neck. Lancet Oncol. 2, 261-269. MACEWEN (E.G.), (A.K.) PATNAIK, (H.J.) HARVEY et al. (1986): - Canine oral melanoma: comparison of surgery versus surgery plus Corynebacterium parvum. Cancer Invest. 4, 397–402. MACEWEN (E.G.), (I.D.) KURZMAN, (S.C.) HELFAND et al. (1994): Combined L-MTP-PE and surgery for canine oral melanoma. Proc. 14th Ann. Conf. Vet. Cancer Soc. 109–110. MATTHIESEN (D.T.) AND (S.M.) MARRETTA (1990): - Results and complications associated with partial mandibulectomy and maxillectomy techniques. Probl. Vet. Med. 2, 248–275. MILLER (T.L.), (G.S.) PRICE, (R.L.) PAGE et al. (1994): - Radiotherapy of canine non-tonsillar squamous cell carcinoma. Proc. 14th Ann. Conf. Vet. Cancer Soc. 20–21. MOORE (A.S.), (G.H.) THEILEN, (A.D.) NEWELL et al. (1991): Preclinical study of sequential tumour necrosis factor and interleukin-2 in the treatment of spontaneous canine neoplasms. Cancer Res. 51, 233–238. MUIR (P.) AND (E.) ROSIN (1995): - Parotid duct obstruction after caudal maxillectomy in a dog. Vet. Rec. 46. 1991a and b). Local recurrence of this tumour is the most common cause of death or euthanasia. Of 104 cases described in the literature, 45% suffered a recurrence (WITHROW and HOLBERG 1981; WHITE et al., 1985; BRADLEY et al., 1986; SALISBURY et al., 1986; KOSOVSKY et al., 1991; SCHWARZ et al., 1991a and b; WHITE, 1991; WALLACE et al., 1992; BURACCO et al., 1994). The mean survival time was approximately 11 months and, depending on the study, only 25 to 50% of the patients survived the first year following surgery. The results of this study are comparable to those already published, although the case number is too small for statistical analysis. Acanthomatous epulides frequently infiltrate bone causing lysis, which clinically and radiographically resembles a malignant tumour. Because they do not undergo metastasis, they are classified as benign or semimalignant. Surgical resection of the mass is normally curative (WHITE et al., 1985; BJORLING et al., 1987; KOSOVSKY et al., 1991; WHITE, 1991). In this study, over an average of 15.5 months there were no cases of recurrence. CONCLUSION This study confirms that the therapy of oral invasive tumours through mandibulectomy or maxillectomy is well tolerated by the patient and the functional and cosmetic results are satisfactory. The prognosis of animals with malignant neoplasia of the oral cavity depends on many factors. They are as follows: (1) the histological tumour type, (2) the duration of disease, (3) the site of the tumour, and (4) the extent of surgical resection. A satisfactory prognosis seems to be possible also in cases where the tumour has already metastasised when adjuvant chemotherapy is performed. In closing it should be stated that oral neoplasia respond well to radiation therapy. Because of the limited availability of this treatment option, no patient in this study underwent such therapy. Fundamentally, radiation therapy is suitable as an adjuvant therapy (squamous-cell carcinoma and oral sarcoma) or as a primary therapy (malignant melanoma, acanthomatous epulides). As this therapy option becomes more and more available to animals, it will play an increasing role in therapy protocols for patients with oral neoplasia. It is to be expected that through the use of all available therapies (surgical resection, radiation therapy, chemotherapy), the survival times of affected patients can be greatly improved. REFERENCES BERG (J.) (1998): - Principles of oncologic orofacial surgery. Clin. Tech. Small Anim. Pract. 13, 38-41. BJORLING (D.E.), (J.N.) CHAMBERS AND (E.A.) MAHAFFEY (1987): - Surgical treatment of epulides in dogs: 25 cases (1974–1984). J. Am. Vet. Med. Assoc. 190, 131–138. BRADLEY (R.L.), (E.G.) MACEWEN AND (A.S.) LOAR (1984): Mandibular resection for removal of oral tumours in 30 dogs and 6 cats. J. Am. Vet. Med. Assoc. 184, 460–463. 82 FECAVA SPONSERED PAPER F eline paediatric medicine Kit Sturgess (1) S U M M A R Y This article aims to look at three important areas of kitten medicine; nutrition, investigation of the stunted kitten and managing the collapsed kitten. The latter two scenarios are common reasons for presenting a kitten for further veterinary advice and investigation. CLINICAL NUTRITION IN KITTENS This paper is based on the FECAVA sponsored lecture given at the PSAVA Annual Congress* Krakow 19-20th November 2005 Choice of supplement – An appropriate supplement should have adequate nutritional density at the recommended dilution (Table 2); too low and it is difficult for a kitten to take in sufficient volume to meet its nutritional needs (stomach volume approximately 70ml/kg). – Hydration is important and concentrated formulae may predispose to dehydration. – Fluid requirements in neonatal kittens are up to 180ml/kg/day hence frequent feeding is required to deliver an appropriate volume of fluid. Cats have unique nutritional needs. Nutritional problems are most likely to occur under periods of maximum demand such as rapid growth, when any dietary deficiencies or toxicities can result in significant disease. Key areas for consideration of nutrition include – Nutritional requirements of orphan kittens – Diets for growing kittens – Nutritional pitfalls Nutritional requirements of orphaned kittens Kittens can require supplementary feeding for a variety of reasons, most commonly due to – Death of the queen during parturition – Failure of the queen’s milk supply – Rejection of one or more kittens by the queen – Litter size is too great for the queen to supply adequate nutrition – Attempts to reduce the risk of infection from a queen known to be FIV or FeLV positive Whilst the ideal substitute is to foster the kitten on to another lactating queen who will accept the kitten this is rarely possible. Queen’s milk is substantially different from bovidae milk (Table 1) and this can not be used as a straight substitute. Home-made and commercial formulae are available (Table 2 and 3). Dry Matter % Protein (%) Fat (%) Sugar (%) Ash (%) Calcium (mg/100g) Phosphorus (mg/100g) Iron (mg/100g) Kcal/100ml Queen Bitch Cow Goat 21 7.5 8.5 4.0 0.6 180 162 0.35 121 13 3.3 3.7 5.0 0.7 115 95 0.2.-0.6 74 12 2.9 3.8 4.7 0.8 0.3-0.4 22.7 7.5 9.5 3.8 1.2 240 180 0.7 146 Table 1 – Comparison of queen’s milk with other milk sources (1)Vet Freedom, Brockenhurst, Hampshire, GB - S042 7QT. E-Mail: [email protected] * Hosted by PSAVA(Poland) 83 Feline paediatric medicine – High osmolality fluids may delay gastric emptying e.g. KMR powder. – Arginine levels can be too low in some formulae and predispose to cataracts (queen’s milk arginine = 430mg/100g or 355mg/100kcal). – Taurine levels need to be sufficient (queen’s milk taurine = 10mg/100g or 8.3mg/100kcal); if the taurine content is unknown, oral supplementation can be given (Figure 2). – All home made recipes should be kept refrigerated and used within 24 hours. – Cream contains high levels of short and medium chain fatty acids and is relatively deficient in linoleic acid. – Queen’s milk is high in albumin compared to casein; however, curd can be used as this contains coagulated casein and not micelles (which are larger in bovine milk than queen’s milk and risks hard coagula forming in the stomach). – Egg whites can cause diarrhoea but are a good source of albumin. – Even the best replacers have potential problems so kittens should be weaned as early as is practicable (from 3-4 weeks). Figure 2 – Echocardiogram of a cat with dilated cardiomyopathy. Queen Dry Matter % Protein (%) Fat (%) Sugar (%) Ash (%) Calcium (mg/100g) Phosphorus (mg/100g) Iron (mg/100g) Kcal/100ml Volume (ml/100kcal) Recipe 1 21 7.5 8.5 4.0 0.6 180 162 0.35 6.25 7.1 3.3 0.5 150 135 0.29 121 83 7.1 4.4 4.7 0.8 96.2 126 0.6 16.9 8.9 5.5 5.9 1.0 120 158 0.75 80 125 Recipe 2 6.4 3.4 2.9 0.7 109 109 3.5 13.6 10.3 5.5 4.7 1.1 176 176 5.6 62 161 KMR powder* www.aah-pets.com 32.6 14.5 9.5 13.3 6.0 6.8 (5.4) 4.5 (3.6) 2.1 1.2 370 244 290 192 1.3 0.8 151 66 Cimicat* www.vetbed.co.uk 5.9 3.9 (5.6) 1.0 175 131 NR 17.5 6.4 4.2 (6.1) 1.1 189 141 NR 92 108 Vital Milk Royal Canin 11 13 (6.2) 2 366 266 NR 33.3 5.9 7 (3.3) 1.1 198 144 NR 186 54 Figures in italics are per 100kcal of metabolisable energy; figures in brackets are % lactulose; * - values are as fed according to manufacturers recommendations Table 2 – Comparison of queen’s milk with milk replacers Recipe 1 Skimmed milk Low fat curd (not cottage cheese) Lean minced beef Egg yolk Vegetable oil Lactulose Vitamin/mineral mix Total Recipe 2 70g 15g 8g 3g 3g 0.8g 0.2g 100g One whole fresh egg Protein supplement* Milk, sweetened, condensed Corn oil Water 250ml 15g 25g 17ml 7ml Total 310g * Protein supplement used was ProBalance Feline (available via www.calvetsupply.com ) – analysis - 47% crude protein, 1% crude fibre and 17% crude fat. The supplement has essential vitamins and minerals, additional nutrients and digestive enzymes. Table 3 - Homemade milk substitutes for kittens 84 KIT STURGESS EJCAP - Vol. 16 - Issue 1 - April 2006 activity than dogs as well as lower levels of diassacharidases making the feeding of a low fat diet more difficult in terms of an alternate source of calories. 3. Cats tend to be more selective eaters and therefore dietary manipulation that results in reduced palatability such as the addition of fibre can have a low acceptance. 4. Carbohydrates are not the major secretagogues of insulin in cats. 5. Cats have an essential requirement for taurine. Taurine deficiency is usually associated with attempts to feed a vegetarian/vegan diet. Taurine deficiency can lead to central retinal degeneration, dilated cardiomyopathy and reproductive failure. In the early stages these changes are reversible. 6. Cats are more sensitive to oxidants in their food which can cause Heinz body anaemia. Such changes have been associated with feeding some baby foods which use onion powder as a base. 7. Cats require a source of preformed vitamin A. 8. Cats have an essential requirement for arachidonic acid in their diet. Feeding orphaned kittens – Attention should be paid to the environment as kittens are unable to thermoregulate (ambient temperature 30-32oC; humidity 55-60%). – Caloric need for kittens is 22-26kcal/100g (most kittens weigh 100-120g at birth) – i.e. a new born kitten needs 18-23ml of queen’s milk per day. – Weight gain of 10-15g/day is ideal. – Feed warm formula (37.8oC) at least 4 times daily depending on the age of the kitten. – Under feed for first feeds gradually increase to full amount over 2-3 days. – Feed using a nipple bottle, dosing syringe or stomach tube. – When using a nipple bottle, milk should slowly ooze from the teat when the bottle is inverted. A drop of milk should be on the teat before inserting into the kitten’s mouth. The milk should be allowed to flow under gravity, squeezing the bottle to increase the flow rate risks aspiration. – Feeding tubes are faster; a 5 FG tube should be used if the kitten is less than 300g. Measure from the nose to the last rib and insert the tube to this length. – After feeding it is vital to stimulate micturition and defecation, this can be done by massaging the anogenital area with moistened cotton wool. – Handling before feeding stimulates exercise promoting muscular and circulatory development. Vegetarian/vegan diets for kittens – It is not possible to formulate vegetarian/vegan diets for cats without careful addition of essential ingredients that are usually animal derived such as taurine and arachidonic acid. – Even when produced, balanced vegetarian/vegan diets do not seem to have the same health benefits as meat-based diets. – Kittens are particularly vulnerable to nutritional deficiencies. Diets for growing kittens Feeding a raw meat diet Once kittens have been weaned they need to be fed a diet suitable for growth. A variety of proprietary diets are available. Kitten diets have higher energy density, protein and vitamin levels than adult maintenance diets. They are usually designed for kitten up until 6 months of age. There are a variety of reasons for making a dietary change at around 6 months as this often coincides with neutering that results in a 20-30% reduction in caloric need. When feeding or formulating a kitten diet, the unique nutritional requirements of cats should be born in mind. Kittens have a higher caloric need than adults although the total volume fed can be small (Table 4). 1. Cats have a higher protein requirement; arginine deficient diets such as some baby foods can rapidly cause hepatic encephalopathy. 2. Cats have significantly lower (about 1/3rd the level) amylase Physiological state < 3 months (growth) 3 - 6 months (growth) 6 - 12 months It has been argued that raw diets are better than cooked diets for cats. No good clinical studies have been performed to address this point. Even raw food is not the same as a freshly killed rodent or bird particularly as it is likely to have been refrigerated or frozen. The greatest risk of feeding raw food is infection whether this is preformed toxins in spoiled foods, bacteria such as Salmonella or parasites such as Toxoplasma. Appropriate sourcing, storage and preparation of raw food are crucial. When feeding raw food, the possibility of cross contamination of human food should also be considered. Nutritional pitfalls Because of their unique nutritional needs some foods are best avoided or given in strict moderation to kittens, these include: Energy requirements (kcal / kg bodyweight) Weight of food required g/kg body weight* Canned diet Dry diet 250 130 80 (neutered) -100 (entire) * 190 * 100 ** 70-90 * based on typical kitten diet - canned (130kcal/100g); dry diet (425kcal/100g) ** based on typical adult diet - canned (110kcal/100g); dry diet (400kcal/100g) Table 4 - Estimated energy requirements in healthy kittens 85 60 30 20-25 Feline paediatric medicine Figure 3- Radiograph showing a marked reduction in bone density in a kitten with nutritional secondary hyperparathyroidism associated with feeding an exclusive lean chicken diet. contain preformed histamine. Ingestion results in reddening of the skin, most noticeably the nose, nausea, vomiting, diarrhoea, abdominal pain and pruritus that develops within 15-60 minutes of ingestion Liver Liver contains excessively high levels of vitamin A leading to painful bone deformities which do not resolve even if the diet is corrected (Figure 4). Milk products Cats generally do love milk but they may lack the enzymes to digest it resulting in large quantities of fermentable sugars reaching the colon leading to osmotic diarrhoea. N.B. Milk is a balanced diet; calcium is NOT in excess hence milk can not be used to balance diets which have excessive phosphorus such as an all meat diet. Figure 4 – Radiograph of the stifle of a cat showing calcification of the soft tissues associated with hypervitaminosis A. Onion-based foods Cats are sensitive to oxidant intoxicants such as onions that are used as a base in some baby foods for example. Table scraps Feeding less than 10% of calories as table scraps is unlikely to cause nutritional imbalance but can lead to obesity if not taken into account when calculating the daily ration. Feeding table scraps can lead to behavioural problems - begging, refusing to eat regular food etc. Pharmacological activity Some foods have pharmacological activity e.g. chocolate but these are rarely consumed by kittens Figure 5 – Severely stunted and septic kitten (on the table) caused by an umbilical infection. This kitten did not survive. Meat and poultry Carnivores in the wild eat the majority of the carcase and not just lean meat which has excessive amounts of phosphorus relative to calcium and is deficient in sodium, iron, copper, iodine and vitamins. An all meat diet can lead to severe and potentially fatal skeletal abnormalities, nutritional secondary hyperparathyroidism (Figure 3) and joint malformations. Fish Raw fish can contain thiaminase which destroys vitamin B1 (thiamine) as well as potentially containing parasites. Excessive amounts of fish can cause a relative deficiency of vitamin E especially if the fish is packed in oil. Fish that has been improperly preserved or inadequately refrigerated, particularly the tuna and mackerel family, can 86 KIT STURGESS EJCAP - Vol. 16 - Issue 1 - April 2006 INVESTIGATION OF THE STUNTED KITTEN Kittens are frequently presented to veterinary surgeons because they are poorly grown (Figure 5). Based on the DAMNIT-V system, the most likely causes of stunted growth are highlighted. D Degenerative; developmental, demented (psychological) A Anomaly (congenital); allergic, autoimmune M Metabolic N Neoplastic, nutritional I Infectious; inflammatory; idiopathic; immune mediated; iatrogenic T Traumatic, toxicity V Vascular Figure 6 – An under grown kitten with an abscess on its head secondary to feline infectious peritonitis. Causes Abnormality of bone growth – Chondrodystrophy Deficient nutrient intake – Inadequate or inappropriate diet – Gastrointestinal parasitism – Persistent vomiting or regurgitation e.g. vascular ring anomaly – Maldigestion / malabsorption Increased caloric demand – Fever – Chronic infectious or inflammatory disease (Figure 6) – Major trauma – Increased caloric loss – Protein losing enteropathy – Protein losing nephropathy – Urine nutrient loss e.g. juvenile onset diabetes mellitus, renal glycosuria Major organ defect – Hepatic - portosystemic shunt, glycogen storage disease (Figure 7) – Renal - dysplasia, pyelonephritis – Congenital cardiac anomaly – Lysosomal storage disease – Endocrinopathy – Hypothyroidism (Figure 8) – Hyposomatotrophism Figure 7 – Six month old male, Havana kitten weighing less 1.7kg and showing neurological signs associated with a portosystemic shunt. Key history – Did the queen have a normal, pregnancy and parturition? – When was the problem first noticed? – Has the kitten been slow and poorly grown since birth? Suggests a congenital defect. – Was the kitten showing normal development (i.e. indistinguishable from the other members of the litter) and then suddenly stopped? Suggests an acquired disease. – Are any other members of the litter similarly affected? – Have kittens in previous litters shown similar signs? – What is the kitten’s diet, appetite and food intake? – Are there signs, other than failure to grow, that indicates major organ disease? – Is the kitten’s body proportionate or disproportionate? – Is the kitten’s body condition good or poor? Figure 8 – Hypothyroidism causing severe reduction in growth rate and skeletal malformation. Physical examination Examination of kittens can be difficult as they rarely stay still and can be aggressive if from a feral background. Neonates tend to show limited responses to disease, initially becoming agitated and crying, progressing to inactivity, hypothermia and loss of the suckling reflex. As with all young animals, changes in their status can be very rapid. Weight gain can be a sensitive indicator of developing problems and can be easily measured by the owner (Figure 9). Failure to gain weight over any 24 hour period is worthy of further investigation. 87 Feline paediatric medicine Daily weight of kittens Weight (grams) FCK Age (days) Figure 9 – Growth curves for a litter of kittens, one kitten’s growth rate began to slow. A few days later this kitten developed a flat chest (Figure 12). – Respiration 15-35 per minute. – Regular rhythm. – Heart murmurs may be innocent, associated with non-cardiac disease (e.g. anaemia, portosystemic shunt) or associated with congenital cardiac disease (Table 5). – Lung sounds difficult to distinguish but should be present; check for symmetry or malformation of the thoracic cavity. External features – Body weight – Hair coat (amount, condition, parasites, persistence of kitten coat) – State of hydration – Signs of injury – Appearance of umbilicus – Discharge from nose/eyes/ears – Urine staining (patent urachus) – Diarrhoea / rectal patency – Congenital malformation Eyes – Kitten’s eyes open between day 5 and day 14. – Pupillary light response is present within 24 hours of opening. – Mild cloudiness of cornea is usually evident at opening but should resolve rapidly. – Swelling under the eyelids indicates pus formation (often staphylococcus spp.), very rarely Chlamydophila felis (Chlamydia psittaci) (Figure 10). Ears – External auditory meatus is closed at birth and opens between 6 and 14 days; check for mites. – Middle ear infection indicated by a bulging tympanum. Mouth – Colour of mucous membrane. – Evidence of cleft palate (Figure 11). Abdomen – Should feel full but not swollen or tight. – Liver and spleen not palpable. – Intestines soft, mobile and non-painful. – Urinary bladder freely movable. Figure 10 – Kitten with serous ocular discharge associated with C.felis infection. Thorax – Shape of thorax - flat chest (Figure 12), pectus excavatum – Heart rate around 200-220 beats per minute. 88 KIT STURGESS Figure 11 – Cleft palate. EJCAP - Vol. 16 - Issue 1 - April 2006 Figure 12 – Flat-chested kitten – this condition develops shortly after birth and particularly affects Burmese kittens. – Acquired diseases tend to be infectious or toxic and therefore other members of the litter are likely to be showing signs. Neurological assessment – Alertness – Response to stimulation – Suckle reflex – Other reflexes appropriate to age – Gait (walking from around 4 weeks old) – Posture – Flexor and extensor dominance appears more variable in kittens than puppies. Diagnostic approach – Is the nutritional and caloric intake adequate? – Is trauma a realistic possibility – if so how is it affecting growth? – Is the problem likely to be a congenital abnormality (if so which organ) or an acquired disease? – Is an endocrinopathy likely – kittens tend to be stunted but otherwise clinically well? – Ensure adequate and appropriate nutrition. – Ensure adequate worming and ectoparasite control. – Haematology, biochemistry and urinalysis to assess major organ disease – Include hepatic function tests (bile acids). – Retrovirus serology. – Survey radiographs - thorax, abdomen, and appendicular skeleton. – Ultrasound and echocardiography – Hormonal tests – growth hormone, thyroid function – Endoscopy and biopsy of the stomach and small intestine. – Fibroblast culture or urinalysis for lysosomal storage disease (Figure 13). – Specific DNA-based genetic tests. Innocent murmurs Congenital murmur Usually I-III/VI, craniodorsal, ejection type Variable with heart rate and body position Often musical Typically diminishing with age & resolving by 16 weeks Usually loud unless – large defect – tricuspid valve dysplasia – mild semilunar valve stenosis May be associated with clinical signs – failure to grow – cyanosis, – exhaustion after brief periods of play – weakness – collapse – Source of congenital murmurs can be difficult to identify in some cats Decision making Table 5 – Characteristics of innocent cardiac murmurs and murmurs associated with congenital heart disease 89 Feline paediatric medicine MANAGING THE COLLAPSED KITTEN History should be focused on – Health of other members of the litter – infectious disease is likely to affect more than one kitten in the litter. – Environment to assess the likelihood of trauma or access to potentially toxic compounds. – Internal or external parasitism is very common. – What parasite control has been used? – Is there a possibility that the parasiticide is causing the problem e.g. piperazine, organophosphates, permethrins? Neonatal responses are relatively limited and body reserves are low so kittens can rapidly change from being bright and well to collapsed and seriously ill. This section will focus on the initial management of the collapsed kitten including physical examination, history taking, basic diagnostics and rational therapy. Physical examination History A thorough physical examination is essential both in order to try and achieve a diagnosis as well as identify urgent problems that require therapy. Normal physiological values for kittens are given in Table 6. Many of the historical questions will be similar to those for the stunted kitten. Congenital diseases can present acutely such as the kitten with a cardiac defect that goes into congestive heart failure or the kitten with a portosystemic shunt that becomes encephalopathic. However, in the majority of cases, trauma, intoxication or infectious disease will be the most likely causes. In such cases, the kitten will have been normally developed, growing and eating well up until the very recent past. Age Rectal Heart rate (days) temperature (bpm) (oF) Respiratory rate (/min) Environmental temperature (oF) 0-7 8-14 15-28 29-35 >35 15-35 15-35 15-35 15-35 Adult 85-90 80 80 70-75 70 96 ± 1.5 100 Adult Adult 200-250 70-220 70-220 70-220 70-220 Investigation of neonatal disease – Routine haematology (Table 7) and biochemistry (Table 8) can be performed from a very early age on blood obtained by jugular puncture (Figure 14). Parameter Kittens (mean or range) Age 0-3 days 2 weeks 4 weeks 6 weeks PCV (%) Haemoglobin (g/dl) RBC (x1012/l) MCV (fl) MCH (pg) MCHC (g/dl) WBC (x109/l) 41.7 11.3 5.11 81.6 24.6 27.3 7.55 25.7-27.3 8.5-8.9 4.57-4.77 52.7-55.1 18.0-19.6 32.5-33.5 14.1-16.5 26.2-27.9 8.3-8.9 5.66-6.12 44.3-46.9 14.2-15.4 31.3-32.5 16.1-18.8 33.6-37.0 11.5-12.7 5.05-5.53 65.5-69.3 22.4-23.6 33.7-35.3 9.1-10.2 Table 6 - Physiological values in young kittens Table 7 - Haematological values in young kittens Parameter Kitten age (weeks) 2 4 7-12 Total protein (g/l) Albumin (g/l) Sodium (mmol/l) Potassium (mmol/l) Chloride (mmol/l) Inorganic phosphate (mmol/l) Calcium (mmol/l) Urea (mmol/l) Creatinine (µmol/l) Cholesterol (mmol/l) ALK-P (U/l) ALT(U/l) Glucose (mmol/l) Bilirubin (µmol/l) Bile acids (µmol/l) 40-52 20-24 <5 4.3-11.6 68-269 11-24 6.08-10.32 1.7-16.9 <10 46-52 22-24 149-153 4.0-4.8 120-124 2.0-2.4 2.4-3.2 <5 36-54 4.6-11.4 90-135 14-26 7.92-8.96 1.7-3.4 <10 51-57 24-32 147-152 5.0-6.2 113-128 2.5-3.1 2.2-2.8 4.2-6.3 36-91 - Table 8 - Serum biochemistry values in young kittens 90 KIT STURGESS EJCAP - Vol. 16 - Issue 1 - April 2006 Figure 13 – An under grown kitten with skeletal abnormalities associated with a lysosomal storage disease. Figure 14 – Jugular venipuncture in a week old kitten. – Many infectious diseases develop too rapidly to obtain results quickly enough (especially bacterial culture and sensitivity or paired serum samples) to be of value to that individual but a knowledge of cause may be beneficial to the rest of the litter or subsequent litters. – To minimise the amount of blood required, glucose can be estimated on a glucometer and 0.5ml EDTA tubes used making a total bleed of 1.5ml in the smallest of kittens sufficient for most tests to be carried out. a lengthening of the interval between doses. – Great care should be taken when administering broadspectrum antimicrobials orally because of their potentially adverse effects on the developing gut microflora. – Subcutaneous and intramuscular absorption of drugs is slower and less reliable than in adults particularly if the kitten is dehydrated. – Antimicrobials administered to the dam do not reach therapeutic concentrations in the milk. – Ensuring adequate nutritional support either by nasooesophageal or gastric intubation is a vital part of therapy particularly in the face of sepsis. Blood volume in cats is estimated at 75ml/kg. A week-old kitten will weigh around 200g and have 15ml of blood – Radiographs can be difficult to evaluate in young kittens as mineralization of the skeleton is poor and the film can be easily over exposed. Reducing the kV to half that used for an adult of similar body thickness should produce radiographs that will provide valuable diagnostic information. – Faecal examinations can be easily performed and are of particular value where protozoan parasites are suspected. Despite aggressive therapy, acutely sick kittens will die and it is important to try and encourage the owner to allow a post mortem examination. Maximum information can be obtained if the carcass is fresh. If a post-mortem can not immediately be performed, the body should be stored in the fridge and not the freezer. A systematic approach should be adopted and all details should be recorded including sex, colour, body weight, amount of body fat, presence of ingesta in the stomach, faeces in the colon and urine in the bladder. Figure 15 – Fluid warmer that can be attached to the giving set line. Consideration affecting the treatment of neonatal disease Special consideration needs to be given when giving drugs or fluids to paediatric patients as they have an immature metabolism, small total body weight but relatively high body surface area. Drugs – Absorption, distribution, metabolism and excretion of drugs can be significantly different from adults. – Few drugs have had dose rates calculated for use in young kittens. – Generally, an increase in the initial dose (/kg) is required with 91 Feline paediatric medicine Fluid therapy Fluid requirements (/kg) are higher in neonates than adults BUT total volumes are low. Young kittens have immature kidneys and lack the ability to concentrate their urine in the face of dehydration and therefore will become dehydrated very quickly especially if there is increased fluid loss such as vomiting or diarrhoea. – Maintenance fluid requirements of very young kittens (less than 2 weeks) are around 180ml/kg/day. By weaning fluid requirements are around 120ml/kg/day. Adult maintenance requirements (50ml/kg/day) are appropriate in kittens over 6 months old. Intravenous – 23g or 25g catheter can be placed in the cephalic vein of many small kittens. – Larger catheters can be placed in the jugular vein but this can be difficult in kittens that are dehydrated. Placing a jugular catheter may required sedation/anaesthesia and cut down. The benefits of jugular access have to be balanced with the risks of placement. – The kitten’s short legs can make the catheter very positional and flow difficult to maintain in gravity fed fluid systems. Forced flow in the absence of syringe or fluid pumps can be achieved using – Battery operated, fixed-rate (0.5 or 1.0ml/hr), single use fluid reservoirs (Figure 16). – Spring-driven, refillable, syringe pumps, flow rate variation is limited and achieved using variable diameter tubing connected to the patient. – Single patient use, refillable balloon infusion devices that use the elastic recoil of the balloon to push the fluid. Flow rate variation is limited and achieved using variable diameter tubing connected to the patient. Example A week old kitten weighing 200g will therefore require 36ml of fluid at maintenance over 24 hours i.e. 1.5ml per hour. Even using a paediatric giving set, this is equivalent to 1 drop every 40 seconds. Increased fluid rates are necessary if the kitten is dehydrated or has increased fluid loss (diarrhoea or vomiting). Fluid should be given at approximately 4ml/kg per episode of vomiting or diarrhoea Intraperitoneal – This route is not ideal as absorption can be relatively slow especially in the face of hypovolaemia and is poorly suited to long-term fluid therapy. However, in the hypovolaemic, collapsed kitten this may be the fastest way of delivering therapy in the short term. – The risks of puncturing viscera are low. – Aseptic technique is mandatory. – Daily fluid requirements should be calculated and the volume divided to be given 2-3 times daily. If the kitten is 8% dehydrated and having episodes of vomiting and diarrhoea every 4 hours then – Maintenance at 1.5ml/hr Fluid deficit is 16ml – replace 50% in the first 6 hours (= 1.3ml/hr) and the remainder over 18 hours (= 0.5 ml/hr) – Increased need associated with GIT signs is 24ml/kg/day = 5ml/day = 0.2ml/hr Fluid rate for first 6 hours is then 3ml/hour (1 drop per 20 seconds) reducing to 2.2ml/hour (1 drop every 27 seconds) These calculations are approximations and it is vital that the state of hydration and urine output is monitored. Intraosseus – Useful where venous access not possible due to vein size or hypotension causing the veins to collapse. – The cortical bone is sufficiently soft in kittens such that a hypodermic needle (18-19g) can be used. – The area should be surgically prepared and the needle placed in either the proximal tibia or proximal femur. Only one attempt should be made at each site since, if the bone cortex – Syringe pumps can be of great value and are significantly cheaper than fluid pumps; otherwise a burette with a paediatric giving set (60 drops per ml) will ensure that the kitten is not over-hydrated. – Kittens will tend to become acidotic associated with many disease states but reduced hepatic function can mean that they are less able to metabolise lactate into bicarbonate. – For most kittens Ringers solution is appropriate. If the kitten is significantly acidotic, bicarbonate can be given separately at 1mmol/kg over 20 minutes. – Glucose can be replaced using a 5% dextrose solution mixed 50:50 with lactated ringers or by giving 1-2ml of 10-25% glucose i/v to profoundly depressed kittens. Figure 16 – Mechanical, low flow rate devices (available from Mila International: www.milaint.com). Methods of drug and fluid administration Kittens are particularly prone to hypothermia so fluids should be warmed before administration. Because the rate of administration of fluids is slow, warming the whole bag of fluid is not effective. Fluid needs to be warmed as it passes through the giving set using a proprietary fluid warmer (Figure 15), heated pads or warm water that is regularly replaced. 92 KIT STURGESS EJCAP - Vol. 16 - Issue 1 - April 2006 is already punctured, it will result in fluid leaking out. – Fluids, drugs or whole blood can be given at the same rates as for i/v therapy. – – – – – Neonatal isoerythrolysis Blood group A kittens are at risk of neonatal isoerythrolysis if they are born to a B group queen. B group cats have naturally occurring, high affinity, anti-A antibodies that are passed to the kitten in the colostrum resulting in immune-mediated haemolytic anaemia. Inadequate colostrum Low birth weight Trauma Neonatal isoerythrolysis Infectious disease Key history – Breeding history of household. – Disease status of household. – Individual breeding history of queen. – Number of kittens born alive and dead. – Health of queen now and during pregnancy. – Status of other litter members. – Status of other kittens in the household. – Recent arrivals / showing / mating. – Pattern of illness to-date. – Health parameters noted by breeder e.g. weight gain. – Hygiene, worming, vaccination and flea control regimes. – Has the kitten ever appeared normal? – Did the kitten ever suckle normally? – Has supplementary feeding been provided (risk aspiration)? – Blood group of queen and stud cat (if known). Clinical signs Kittens start to fade when they are a few days of age. Owners first notice discoloration of the urine due to haemoglobinuria. Kittens will become jaundiced. Tail and ear tip necrosis will also occur. Blood group distribution by breed in the UK NB – blood group distribution in other areas of Europe may be different from this Breeds with no type B cats – Siamese, Burmese, Tonkinese, Oriental short hair, Ocicat Breeds with <5% type B cats – DSH, DLH, Maine Coon, Norwegian Forest Cat Breeds with 10-20% type B cats – Abyssinian, Birman, Himalayan/Persians, Scottish fold ear, Somali, Sphinx Breeds with >20% type B cats – British and exotic short hairs, Cornish and Devon rex Investigation A full physical examination should be performed including a neurologic assessment for alertness, suckle reflex, response to noxious stimuli and reflex responses (not fully developed until 12 weeks). Decision making – Level of problem - household, litter or individual. – Congenital vs. hereditary? – Infectious vs. anatomic? – Likelihood of trauma? – Possibility of neonatal isoerythrolysis? Therapy Aggressive therapy needs to be given at an early stage and blood transfusion with group A blood is necessary. Mortality rates can be high. Prevention Subsequent matings of the queen should with a B group stud cat. If this is not possible then the kittens should be blood grouped (jugular sample or umbilical blood) at birth before they are allowed to suckle and A or AB group kittens given A group colostrum (usually requires fostering onto an A group queen) or milk replacer until after gut closure (24 hours). In kittens given milk replacer, the lack of colostrum will, however, make them vulnerable to other infectious diseases. This risk can be reduced by feeding 1-3ml of serum from a type A cat. Ideally queens and stud cats should be blood typed prior to mating. Diagnostic investigation – Routine haematology and biochemistry – Faecal and urinalysis – Bacterial culture – Serology – A positive FIV test can not be interpreted in a neonate because of passive transfer of antibodies from the queen. A kitten born to an FIV antibody negative queen is highly unlikely to have FIV. – Imaging studies – Biopsy / post mortem Fading kittens Blood transfusions Definition These are typically kittens born apparently healthy that either fail to suckle (or lose their suckle reflex) and die with no organspecific clinical signs. Fading kittens may occur as single cases; affect multiple or all kittens in the litter. Kittens can survive with a very low haematocrit and can present with a PCV as low as 6-8%. These kittens are very vulnerable to stress and need to be handled carefully and pre-oxygenated before attempting to take blood or place an i/v line. Where severe anaemia is suspected, a small amount of blood is required to blood type the kitten and measure their PCV. If the kitten is symptomatic or has a PCV of less than 12%, blood transfusion is appropriate and can be very rewarding. Only small volumes of blood are required but can result in dramatic clinical improvement. Common causes – Congenital abnormality – Exposure to teratogens in utero – Inadequate nutrition 93 Feline paediatric medicine Blood volume required REFERENCES AND FURTHER READING Example A 200g kitten (7 day old) presents with a PCV of 8%. A group matched blood donor is available whose PCV is 30%. Target PCV is 25% for the kitten Volume required = Desired PCV (L/L) – Actual PCV (L/L) x 100 x bodyweight (kg) PCV of donor (L/L) HOSGOOD (G.), HOSKINS (J.D.) (1998) - Small Animal Paediatric Medicine and Surgery, Butterworth Heinemann, Oxford. IHLE (S.L.) (2005) - Failure to Grow in Textbook of Veterinary Internal Medicine [6th edition]; Ettinger, S.J. & Feldman, E.C. eds. Elsevier Saunders, Missouri, pg. 80-82. JACOBS (R.N.), PAPICH (M.G.) (2000) - in Kirk’s Current Veterinary Therapy XIII; Bonugura, J. ed. W.B.Saunders, Philadelphia, pg. 1211-1212. KIRK (C.A.), DEBRAEKELEER, (J.), ARMSTRONG (P.J.) (2000) Normal Cats in Small Animal Clinical Nutrition [4th edition]; Hand, M.S., Thatcher, C.D., Remillard, R.L. & Roudebush, P. eds. Walsworth Publishing Company, Missouri, pg. 329-334. STURGESS (C.P.) - (1998) Infectious Disease Of Neonates, Young Puppies & Kittens in BSAVA Manual of Small Animal Reproduction & Periparturient Care, pg.159-166. STURGESS (C.P.) (2003) - Feline Internal Medicine, Blackwells, Oxford, pg 27-28, 35-36, 313-319. = 0.25 – 0.08 x 100 x 0.2 = 11ml 0.30 Blood collection Blood can be collected in 10-20ml syringes pre wetted with acid citrate dextrose solution (1ml/10ml of blood collected) via a 21g butterfly catheter placed in the jugular vein of a donor cat. In some cases mild sedation of the donor [e.g. ketamine (5mg/kg) and midazolam (0.25mg/kg)] may be necessary. Alpha2adrenergic agonists such as medetomidine should be avoided due to their hypotensive effects making venipuncture difficult. Donor cats should be clinically healthy, less than 8 years old and ideally have been tested negative for FeLV, FIV and FIA (feline infectious anaemia). Performing the transfusion Blood should be administered via an intravenous or intraosseus route using a T-connector or low volume extension tubing (23ml) to minimise dead space. Blood should be given at an initial transfusion rate of half maintenance for the first half hour in the non-emergency situation. In reality, for most kittens this means a bolus of 0.5 ml and waiting for half an hour to see whether there is an adverse reaction. Thereafter blood can be given at twice maintenance. In an emergency, blood can be given at shock rates (70ml/kg/hour) – for the kitten in the example above, this means giving the 11ml needed over about 45 minutes. CONCLUSIONS Kitten medicine is a truly challenging but very rewarding area for the veterinarian. The small size of the patient, speed with which they deteriorate and lack of localising clinical signs makes investigation and treatment difficult. The value of success, however, is great in the hope that your patient will survive and enjoy the next 15 year or so of life. ACKNOWLEDGMENTS Professor T.J. Gruffydd-Jones for Figures 8 and 11 Dr D. Gunn-Moore for Figures 6 and 13 Mrs R. Giles for Figure 1 94 REPRINT PAPER (CH) A utochthonous infections with Angiostrongylus vasorum in dogs in Switzerland and Germany S. Staebler(1), H. Ochs(1), F. Steffen(3), F. Naegeli(4), N. Borel(2), N. Sieber-Ruckstuhl(3), P. Deplazes(1) S U M M A R Y Angiostrongylus vasorum is endemic in foxes and other carnivores in the south and south east of France, Denmark and Great Britain. The reddish nematode is present in the pulmonary arteries and the right side of the heart and causes respiratory and cardiovascular signs. From 1999 to 2004, A. vasorum was diagnosed in three dogs from southern Switzerland, five dogs from northern Switzerland and in one dog from southern Germany. There were variable clinical signs in the affected dogs including coughing, tachypnoea and dyspnoea. Two of the dogs had neurological signs. Four of these dogs died and diagnosis was confirmed by necropsy. Diagnosis in the other five dogs was achieved by detecting the larvae in faeces. Based on the case history at the time of presentation, these nine dogs were probably autochthonous cases. Key words: Angiostrongylus vasorum – epidemiology – central Europe INTRODUCTION This paper originally appeared in: Schweiz.Arch.Tierheilk* 2005 147(3) p121-p127 up to 5 years (Eckert and Lämmler, 1972). Occasionally, the larvae can be found in the left side of the heart, the kidneys, the anterior chamber of the eyes and in the brain (Bolt et al., 1994). Infected dogs develop various respiratory and cardiovascular signs such as coughing, tachypnoea, dyspnoea, cardiac dilatation, ascites and hydrothorax (Bolt et al., 1994). Often a consumptive coagulopathy can be observed which results in anaemia and subcutaneous haematomas. In rare cases, neurological manifestations such as depression, ataxia, paralysis and epileptiform seizures have been described (Capdebielle and Hussenet, 1911; Patteson et al., 1993; Perry et al., 1991; Reifinger and Greszl, 1994; Tinapp, 1969). Severe clinical manifestations occur mostly in animals in their first year of life (Eckert and Lämmler, 1972). Without treatment the infection can be fatal. Angiostrongylus vasorum is a parasitic nematode with an indirect life cycle. Foxes and dogs are final hosts and gastropods (snails and slugs) obligatory intermediate hosts (Guilhon, 1963; Guilhon, 1965; Guilhon and Bressou, 1960). After ingestion of an infected intermediate host, the third stage larvae migrate via the abdominal visceral lymph nodes into the blood. The adults lodge within the pulmonary arteries and the right side of the heart and start to produce eggs (Rosen et al., 1970). The eggs reach the pulmonary arterioles via the bloodstream and develop into first stage larvae. These penetrate the alveoli, are coughed up into the pharynx, swallowed and shed in the faeces of the final host. The prepatent period is between 40 and 49 days. Infected dogs can remain patent for (1) Institute of Parasitology, (2) Institute of Veterinary Pathology, (3) Clinic for Small Animals, University of Zurich, Winterthurstrasse 266a, CH-8057, Zurich, (4) Studio Veterinario, Balerna. E-mail: [email protected] (Dr Staebler), [email protected](Prof Deplazes) * Presented by SVK/ASMPA (Switzerland) 95 Autochthonous infections with Angiostrongylus vasorum in dogs ANIMALS, MATERIALS AND METHODS A. vasorum is mainly transmitted in wildlife using the fox as its final host. The geographical distribution in both foxes and dogs is sporadic and focal. In Europe, endemic foci exist in Italy, south-west France, Ireland, south-west England (Bolt et al., 1994) and Denmark (Bolt et al., 1992). Of 509 foxes investigated in Italy, 39% were infected with A. vasorum (Poli et al., 1991). A similar prevalence (36%) was demonstrated in 39 foxes in Denmark (Willingham et al., 1996). Sporadic autochthonous cases have been reported from France, south-east England, Switzerland, Spain and the former Soviet Union (Bolt et al., 1994). Faeces and/or nematodes found during necropsy and formalinfixed tissues from nine dogs were examined for the presence of A. vasorum. The first stage larvae were extracted from faeces by the Baermann technique (Eckert, 2000). Identity was confirmed by the larval length (310-400 μm) and the typical structure of the tail with a dorsal cuticular spine (Deplazes, 2005). Adult nematodes found in the heart were confirmed as A. vasorum by their typical morphology (male: 14-18 mm long, slightly reddish, terminal end slightly enrolled with a small bursa and two long spicules (360-400 μm); female: 18-25 mm long, vulva shortly before the anal opening, red intestines) (Deplazes, 2005). There are only a few reports of autochthonous cases of angiostrongylosis in central Europe. Wolff (1969) diagnosed A. vasorum in a dog breeding establishment near Zurich with up to 51% of slugs (Arion rufus) infected with larvae of A. vasorum. Recently, two infected foxes were detected in Basel (Gottstein, 2001; [email protected]). Tissues taken during necropsy and fixed in 10% formalin were processed for routine histology. In three cases the larvae could be demonstrated by HCl-pepsin digestion (modified Trichinella technique) (Eckert, 2000) of formalin-fixed tissues. In brief, tissues (5g/l) were minced mechanically and digested in an HCl solution (1% v/v) with pepsin (5g/l) in a water bath at 45°C with shaking. After four to eight hours of incubation (time depending on the kind of tissue and its fixation in formalin) the suspension was sieved and sedimented two times for 20 mins. The sediment was carefully examined microscopically for the presence of adults and larvae. Canine angiostrongylosis has also occurred sporadically in imported dogs (Ribière et al., 2001). In addition, larvae of A. vasorum were detected in nine out of 8438 samples in a private laboratory near Freiburg i. Br. (Barutzki and Schaper, 2003). In 7 cases the dogs originated from different parts of Germany (Nordrhein-Westfalen, Hessen, Saarland, Bayern and BadenWürttemberg) (Dr. D. Barutzki, personal communication). In this article we report nine presumably autochthonous cases of angiostrongylosis in southern and northern Switzerland and the adjacent German border area. Table 1: Clinical data, necropsy- and histological findings as well as parasitological results Case nr Breed, age and sex (diagnosis) 1 Sheep dog, 5 years old, Cough after effort m (11.1999) Dogo Argentino, Inappetence, apathy, ataxia 10 months old, f (01.2000) 2 Clinical symptoms - First larvae in faeces (MT) Interstitial pneumonia, arteritis, meningitis, encephalitis Bleeding into thorax, lung, thymus, pericard, mediastinum; granulomas in the lung - Adults in heart (N), A. pulmonalis (N), lung (H); larvae in the brain (H) Adults and first larvae in lung (D), third larvae in thymus (D) First larvae in faeces (MT) Cough, slightly pneumonia Bronchointerstitial pneumonia with bleedings, interstitial nephritis, bleedings and malacia in the brain - First larvae in lung and kidney (D); first larvae in the intestine (SF) First larvae in faeces (MT) Cough, tachypnœa - First larvae in faeces (MT) Clearing throat after activity - First larvae in faeces (MT) Cough, dyspnea Pneumonia with sections of adults First larvae in lung (D) 3 Labrador, 1 year old, f (01.2002) Cough, nose bleeding 4 Poodle, 1 year old, f (02.2002) Labrador, 1 year old, f (06.2002) Cough 5 6 7 8 9 Lagotto Romagnolo, 6 months old, m (11.2002) Scottish Terrier, 2 years old, m (09.2003) Labrador, 9 years old, m (12.2003) Maltese, 8 months old, f (01.2004) necropsy and histological results Parasitological proof Swollen eyes, ataxia, cramps m: male; f: female; -: not done, N: necropsy; H: histology; D: digestion; MT: migration technique; SF: sedimentation/flotation 96 S. STAEBLER EJCAP - Vol. 16 - Issue 1 - April 2006 7 8 4 2 6 1 5 9 3 Figure 1: Geographical distribution of dogs (cases 1-9) with Angiostrongylus vasorum-infections. RESULTS With the exception of dog 9, which died before treatment commenced, cases 1, 4, 6 and 7 were successfully treated either with fenbendazole (Panacur®) whilst case 8 was treated with milbemycin and praziquantel (Milbemax®). Faecal examination two weeks after treatment was negative in all dogs. Only dog 8 had a history of travel outside the area. This animal had been to southern France, Burgundy and Alsace. Three of the six presented dogs were known to eat snails or slugs. One dog, which did not have a history of eating snails or slugs, was known to eat fallen fruit. During the past five years, A. vasorum infection was diagnosed in five dogs from northern Switzerland, in one dog from the Swiss-German border region and in three dogs from southern Ticino close to the Italian border (Figure 1). In five dogs angiostrongylosis was diagnosed by faecal examination and the animals were treated. Four dogs died and the diagnosis was confirmed by necropsy. In three of these dogs the digestion of formalin-fixed tissues was required. We present six cases with similar clinical signs and three further cases separately. Detailed data for the individual dogs, including the breed and age, clinical signs, necropsy, histological and parasitological results are summarised in Table 1. Case 2: A 10 month old entire Dogo Argentino bitch presented with innappetence, salivation and retching followed by disorientation. This progressed to impaired consciousness with apathy and general ataxia. There was no improvement despite fluid therapy, antibiotics and non-steroidal anti-inflammatory drugs. The animal became comatosed and died after four days. At necropsy, masses of dark red, adult A. vasorum up to 2 cm long could be found in the right side of the heart and the larger branches of the pulmonary arteries. Histology revealed a high degree of diffuse, chronic to active and interstitial pneumonia with necrotising arteritis, caused by parasitic thrombosis. In the larger pulmonary arteries, adults were found and masses of eggs in the alveoli. The changes in the brain consisted of diffuse, purulent meningitis and perivascular encephalitis. In the brain there were multiple small foci of haemorrhage and necrosis. Larvae were visible in the neuropil. Cases 1, 4, 6, 7, 8 and 9: These dogs had respiratory signs (Table 1), which varied between cases only in duration and intensity. In addition, dog 8 had thrombocytopenia and prolonged bleeding after a tooth extraction. In five of these animals diagnosis was confirmed by demonstrating larvae in the faeces. Dog 9 died and larvae were demonstrated at post mortem by digestion and histology of lung tissue. In addition to angiostrongylosis, three dogs (cases 1, 4 and 7) had a co-infection with Crenosoma vulpis. Dog 7 was also infected with Ancylostoma and Taenia spp. Echinococcus multilocularis was excluded by PCR examination of the taeniid eggs (Mathis et al., 1996). 97 Autochthonous infections with Angiostrongylus vasorum in dogs This animal belonged to a dog breeding unit, had a history of eating slugs and snails and had never left Switzerland. Faecal samples from the remaining dogs on the unit tested negative for the presence of A. vasorum. The experimental infection of dogs with A. vasorum with infested snails has been demonstrated (Bolt et al., 1992). The parasite can be introduced into new areas by the importation of infected dogs. It is believed that the introduction of the parasite into Denmark was by dogs originating from France (Bolt et al., 1992). In a parasitological investigation of 100 red foxes in Denmark in 1973, A. vasorum was not detected (Guildal and Clausen, 1973). Twenty years later this parasite had become established in the fox population around Copenhagen (C.M. Kapel, personal communication). Cases of angiostrongylosis are now frequently diagnosed (Bolt et al., 1992). Case 3: A one year old neutered Labrador bitch from southern Ticino was presented with a cough and was treated with antibiotics. Two weeks later, the dog presented with peracute shock, coughing and nasal haemorrhage. Haematologically the bitch had a slightly regenerative anaemia. Despite treatment with antibiotics and corticosteroids the animal died 12 hours later. Post mortem findings included pulmonary, pericardial, mediastinal and thymic haemorrhage. Histology revealed a granulomatous pneumonia with masses of giant cells and isolated sections of A. vasorum larvae. In the present report, six dogs were from the region of Basel/Aargau (Fricktal) and the adjacent region of southern Germany (Figure 1). In this area (Basel-Stadt) A. vasorum was demonstrated in two foxes, which suggests the parasite is endemic (Gottstein, 2001, [email protected]). Because the fox population is increasing, especially in urban areas of central Europe (Chautan et al., 2000; Deplazes et al., 2004), the distribution of the parasite could increase. The slug Arion rufus is a known intermediate host in central Europe (Eckert and Lämmler, 1972), but other snail or slug species as well as the common frog (Rana temporaria) are potential intermediate hosts (Bolt et al., 1993; Eckert and Lämmler, 1972; Guilhon and Cens, 1973). Among our nine dogs, three were known to eat slugs. In digested lung and thymic tissue one first and two third stage larvae of A. vasorum were found respectively. In the brain, liver and kidneys as well as in the coagulum from the heart no larvae could be detected. The dog originated from southern Ticino and had briefly visited the adjacent area in northern Italy. Case 5: A one year old entire Labrador retriever bitch was presented with lameness and weakness of the hind legs. Additionally, the bitch salivated and had swollen eyelids. The rear left tarsus was swollen with a small wound. A day later the bitch showed generalised ataxia, muscular spasms and anal bleeding. Haematology revealed a slight anaemia and leucocytosis. Despite fluid therapy, antibiotics, spasmolytics, anti-tetanus serum and corticosteroids the animal died within two days. The clinical presentation of the nine dogs varied. Older dogs had a slight cough, especially after exercise. In contrast, dogs one year old or less had severe clinical signs and some died. Bolt (1994) suggested that slugs are eaten especially by young dogs and fox puppies, and this could explain the severe course of the disease. Two dogs died within a few days showing neurological signs. Such an acute presentation, together with neurological signs, is unusual (Bolt et al., 1994). The histological changes consisted of an extensive, diffuse, broncho-interstitial pneumonia, diffuse haemorrhage and numerous larvae. In the kidneys, parasite sections were present together with mild, patchy interstitial nephritis. Changes in the brain and meninges consisted of small foci of acute haemorrhage and malacia. Two other dogs died due to parasitic infection after coughing for two weeks. These animals were not diagnosed clinically and consequently were treated with antibiotics only. This demonstrates the importance of a correct diagnosis and appropriate anti-parasitic therapy. In the intestinal contents, first stage larvae of A. vasorum and Trichuris eggs were recovered by sedimentation/flotation technique. The digestion of lung tissue demonstrated large numbers of first stage larvae of A. vasorum. In digested kidney tissue only two first stage larvae were recovered. No larvae could be found in digested heart, brain and liver tissue or in the anterior chamber of the eye. In individual cases coagulation abnormalities with consumptive coagulopathy and thrombocytopenia occurred leading to a haemorrhagic diathesis manifested by anaemia, haemoptysis, melaena and subcutaneous haematomas (Bolt et al., 1994). Excessive bleeding after the excision of a tooth, epistaxis and bleeding into the thorax was reported in two of the dogs. The diagnosis of A. vasorum is made by the demonstration of first stage larvae in faeces or in washings from bronchoalveolar lavage. As the larvae are not shed continuously, negative dogs should be retested. Larvae of Crenosoma vulpis can be clearly distinguished morphologically. Capillaria aerophilia also causes respiratory signs, but can be distinguished by the characteristic eggs using sedimentation/flotation techniques (Deplazes, 2006). A serological test for angiostrongylosis is not presently available. As in case 3 this animal originated from southern Ticino but had visited northern Italy. DISCUSSION The distribution of A. vasorum in central Europe has been incompletely investigated, but several case reports from Germany and Switzerland document its existence. From different endemic regions it is known that foxes are the most important final hosts (Bolt et al., 1992; Poli et al., 1991). Angiostrongylosis can be treated with fenbendazole 50 mg/kg daily for five days or 20 mg/kg two times daily for 2-3 weeks 98 S. STAEBLER (Deplazes, 2006). Mebendazole at a dose of 50-100 mg/kg orally two times daily over five to 10 days is also effective (Bolt et al., 1994). Milbemycin, 0.5 mg/kg orally once a week for four weeks, was effective in 14 out of 16 dogs (Conboy, 2004). Antigens released during therapy (anaphylactic shock) and dead adult stages (emboli) can cause side effects. REFERENCES BARUTZKI (D.), SCHAPER (R.) - Endoparasites in dogs and cats in Germany 1999-2002. Parasitol. Res. 2003, 90:148-150. BOLT (G.), MONRAD (J.), FRANDSEN (F.), HENRIKSEN (P.), DIETZ (H.H.) - The common frog (Rana temporaria) as a potential paratenic and intermediate host for Angiostrongylus vasorum. Parasitol. Res. 1993, 79:428-30. BOLT (G.), MONRAD (J.), HENRIKSEN (P.), DIETZ (H.H.), KOCH (J.), BINDSEIL (E.), JENSEN (A.L.) - The fox (Vulpes vulpes) as a reservoir for canine angiostrongylosis in Denmark. Field survey and experimental infections. Acta. vet. scand. 1992, 33:357-62. BOLT (G.), MONRAD (J.), KOCH (J.), JENSEN (A.L.) - Canine angiostrongylosis: a review. Vet. Rec. 1994, 135:447-52. CAPDEBIELLE, HUSSENET: Embolie cérébrale produit par Strongylus vasorum. Rev. Vét. 1911, 36:144-147. CHAUTAN (M.), PONTIER (D.), ARTOIS (M.) - Role of rabies in recent demographic changes in Red Fox (Vulpes vulpes) populations in Europe. Mammalia. 2000, 64:391-410. CONBOY (G.) - Natural infections of Crenosoma vulpis and Angiostrongylus vasorum in dogs in Atlantic Canada and their treatment with milbemycin oxime. Vet. Rec. 2004, 155:16-18. DEPLAZES (P.) - Helminthosen von Hund und Katze. In: Veterinärmedizinische Parasitologie. Hrsg. T. Schnieder, Parey Buchverlag Berlin, 2006. DEPLAZES (P.), HEGGLIN (D.), GLOOR (S.), ROMIG (T.) Wilderness in the city: the urbanization of Echinococcus multilocularis. Trends. Parasitol. 2004, 20:77-84. ECKERT (J.) - Helminthologische Methoden. In: Veterinärmedizinische Parasitologie. Hrsg. M. Rommel, J. Eckert, E. Kutzer, W. Körting und T. Schnieder, Parey Buchverlag Berlin, 2000, 69-84. ECKERT (J.), LÄMMLER (G.) - Angiostrongylose bei Mensch und Tier. Z. Parasitenkd. 1972, 39:303-322. GOTTSTEIN (B.) - Lungenwurm Angiostrongylus vasorum bei einem Fuchs in der Schweiz. BVET-Magazin. 2001, 1:22. GUILDAL (J.A.), CLAUSEN (B.) - Endoparasites from one hundred Danish red foxes (Vulpes vulpes (L.)). Norweg. J. Zool. 1973, 21:329-330. GUILHON (J.) - Recherches sur le cycle évolutif du Strongle des vaisseaux du chien. Bull. Acad. Vét. 1963, 36:431-442. GUILHON (J.) - [Larval development of Angiostrongylus vasorum (Baillet, 1866) in the Arionidae organism]. C. R. Acad. Sc. 1965, 261:4225-7. GUILHON (J.), BRESSOU (C.) - Rôle des limacidés dans le cycle évolutif d’Angiostrongylus vasorum (Baillet, 1866). C. R. Acad. Sc. 1960, 251:2252-2253. GUILHON (J.), CENS (B.) - Angiostrongylus vasorum (Baillet, 1866): Étude biologique et morphologique. Ann. Parasitol. Hum. Comp. 1973, 48:567-596. MATHIS (A.), DEPLAZES (P.), ECKERT (J.) - An improved test system for PCR-based specific detection of Echinococcus multilocularis eggs. J. Helminthol. 1996, 70:219-222. PATTESON (M.W.), GIBBS (C.), WOTTON (P.R.), DAY (M.J.) Angiostrongylus vasorum infection in seven dogs. Vet. Rec. 1993, 133:565-70. EJCAP - Vol. 16 - Issue 1 - April 2006 PERRY (A.W.), HERTLING (R.), KENNEDY (M.J.) - Angiostrongylosis with disseminated larval infection associated with signs of ocular and nervous disease in an imported dog. Can. Vet. J. 1991, 32:430-431. POLI (A.), ARISPICI (M.), MANCIANTI (F.), ABRAMO (F.) Pathology of naturally acquired Angiostrongylus vasorum infection in the red fox (Vulpes vulpes). Angew. Parasitol. 1991, 32:121-6. REIFINGER (M.), GRESZL (J.) - Pulmonale Angiostrongylose mit systemischer Ausbreitung und zentralnervaler Manifestation bei einem Hund. J. Vet. Med. B. 1994, 41:391-398. RIBIERE (T.), GOTTSTEIN (B.), HUBER (E.), WELLE (M.), FORSTER (J.L.), GROSCLAUDE (P.) - A propos d’un cas d’angiostrongylose canine. Schweiz. Arch. Tierheilkd. 2001, 143:313-318. ROSEN (L.), ASH (L.R.), WALLACE (G.D.) - Life history of the canine lungworm Angiostrongylus vasorum (Baillet). Am. J. Vet. Res. 1970, 31:131-43. TINAPP (D.) - Über das Wirt-Parasit-Verhältnis bei der experimentellen Infektion des Hundes mit Angiostrongylus raillieti (Travassos, 1927). Dissertation. Justus Liebig-Universität, Giessen, 1969. WILLINGHAM (A.L.), OCKENS (N.W.), KAPEL (C.M.), MONRAD (J.) - A helminthological survey of wild red foxes (Vulpes vulpes) from the metropolitan area of Copenhagen. J. Helminthol. 1996, 70:259-63. WOLFF (K.), ECKERT (J.), LEEMANN (W.) - Beitrag zur Angiostrongylose des Hundes. In: Vortrag Tagung Fachgr. ”Kleintierkrankheiten”, Dtsch. Vet.-med. Ges, Zürich, 1969. AVEPA (Spain) leads the way AVEPA and the IVEE (Institute for Veterinary Economic Studies) develop the first MBA Programme for Veterinary Practices Managers in Europe For the first time in Europe, small animal Veterinariarians will be able to obtain an official MBA degree specifically designed for Veterinary Practice Managers. This MBA Programme, which started its first course in the city Barcelona in October 2005, is a joint initiative of AVEPA and the Universitat Autònoma de Barcelona (home of the College of Veterinary Medicine).The course language will be Spanish, but Practice Managers and Veterinarians from all over Europe will be welcome to enrol. This two year programme is composed of eight modules with the following structure: First Year: Introduction courses in Human Resources), Finance, Marketing and Strategy. Second Year: Advance courses in Human Resources, Finance, Marketing, and Strategy. After the completion of the first four modules successful participants receive an official Diploma of Veterinary Practice Management. When all of the eight modules in the programme have been completed qualifying students will receive their official Masters in Veterinary Practice Management (an official title from the Universitat Autònoma de Barcelona). Classes will take place on a “one day per week – six hours per day” basis (Wednesdays in Barcelona, Thursdays in Madrid) over the period October-May for two consecutive years. This initiative is the result of AVEPA’s follow-up from the findings of the 2004 Practice Management Report, where the lack of managerial resources and capabilities among practicing veterinarians was identified as one of the factors limiting the profitability of veterinary businesses. The Programme will combine academic rigour with relevant professional experience in the veterinary industry. The teaching methods will be predominantly practical, combining lectures with cases and practical exercises specifically designed for circumstances pertaining in small animal veterinary practices. A brief description of the outline of the syllabus is detailed below: 1) Human Resources: – Practice Team management – Self-Appraisal as a leader, and leadership capabilities development – Emotional Intelligence in the context of a Veterinary Hospital – Performance Appraisal systems in a Veterinary Hospital – Compensation Policies in a Veterinary Hospital – Staff recruitment, training, motivation and retention in a Veterinary Hospital – Conflict resolution, negotiation, meeting management... – Delegation 2) Finance: – Financial Accounting Statements (Balance Sheet, Profit and Loss, Cash Flow statement) – Management Accounting: profitability analysis, cost analysis, pricing techniques – Financial Analysis: financial diagnostics, financial and operating ratios, treasury management, budgeting – Financing sources – Investment Analysis – Practice Valuations – Value Creation for a Veterinary Hospital 3) Marketing: – – – – – – – – – – Local Scope Marketing Health Services Marketing Pricing Policies and Marketing Implications for a Vet Hospital Customer Service (phone, reception, in the consultation room...) Personal communication technques for the veterinarian Merchanding at the vet hospital Complaint management at the vet hospital CRM: relational marketing at the vet hospital Client Satisfaction: measurement, tracking and interpretation in the vet hospital Advertising in the vet hospital 4) Strategy and Planning – Business Plan for a Vet Hospital – Balanced Score Card for a Vet Hospital – Financial and Operating Ratios (AVEPA Practice Management Report 2004) – The role of the Practice Manager – Organizational Architecture at the Vet Hospital – Management Information Services in the Vet Hospital – Process definition and standarization – Competitive Strategies for Veterinary Hospitals – Growth Strategies for Veterinary Hospitals – Succession, retirement, selling-out... – Business Ethics for veterinarians For further information contact AVEPA E-mail: [email protected] Editors note The use of the words ‘Veterinary Hospital’ in the above report encompasses Veterinary Practices employing a manager. COMMISSIONED PAPER P atterns in Practice ownership: a UK perspective F. J. Marshall(1) B A C K G R O U N D Veterinary practices in the United Kingdom were formerly often based in market towns in agricultural areas. Companion animal practice was usually carried out as an adjunct to agricultural practice. With the increase in pet ownership during the second half of the twentieth century some genuinely mixed practices, whilst remaining as agricultural practices, began to provide more specialised companion animal services often with veterinary surgeons dedicated to the latter. In addition many new practices developed devoted solely to companion animals. Some of these became very sophisticated in the services offered. The concept of the Veterinary Hospital developed throughout the latter half of the century with practices offering highest quality services with round the clock availability of such quality services, using resident nursing staff employed to care for in-patients and who could summon veterinary surgeons when required. Many other practices offered at their central site a high level of daytime service equalling the level of service of Veterinary Hospitals but did not provide resident night-time care. Some offered services during limited hours at branch surgery sites with any in-patient services provided at the central surgery. Some Veterinary Hospitals equally offered centralised hospital standard care for their transferred branch-surgery patients. OWNERSHIP This paper was commissioned by FECAVA for publication in EJCAP Ownership of practices in Great Britain has traditionally varied from one veterinary surgeon, often employing others, to partnerships of several veterinary surgeons, again often employing other veterinary surgeons. Whatever the pattern, ownership of practices always remained in the hands of veterinary surgeons as the regulations of the governing (statutory) body, the Royal College of Veterinary Surgeons (RCVS), forbade any alternative. Management of practices was generally carried out by one or more of the partners. They were seldom (with a few exceptions) experienced in management, either in respect of financial or personnel (staff) matters. As long as the practice appeared to be profitable and sufficient income was obtained to enable the partners to enjoy whatever lifestyle they wished, the practice was assumed to be successful, to be ‘doing OK’. During the sixties and seventies there grew a greater awareness of commercial business realities. No longer could services be provided without an appreciation of the need for commercial success of a veterinary practice as a business. Practices could not continue to give indefinite free credit to local farmers just because his family had been clients for many years. Some practices responded to these pressures by recruiting ‘Practice Managers’ who had management experience but, initially, little knowledge of the realities of veterinary practice. Others enabled partners (or employees) to learn and then implemrnt management practises whilst remaining employed within the practice. From this concept has developed the, now very well founded, Veterinary Practice Management Association. (1) F. J. Marshall B.V.M.S. M.R.C.V.S. 2 Lake View, Wakefield , GB-WF27SN 101 Patterns in Practice ownership: a UK perspective REGULATORY CHANGES Whilst taxation issues impinged on the owners of some larger practices or groups, leading them to look at other options of ownership, the RCVS continued to maintain that ownership of a practice could only be by individual veterinary surgeons, either singly or in partnership. As far as the RCVS was concerned, any disciplinary action by RCVS for infringement of rules of professional conduct could only be taken against an individual veterinary surgeon and not against a partnership or against any company which owned a veterinary practice. During the last decade of the century, commercial pressures upon some practices led to their wishing to become incorporated as Limited Companies. The RCVS, having taken legal advice, relaxed its regulations to allow companies and nonveterinary surgeons to own practices. Whilst many practices remain in traditional veterinary ownership a number of new models have emerged. Picture 2: ‘A neutering and vaccination Clinic’ which, whilst containing veterinary practices, offer what is conceived as a one-stop shop for pet owners (Picture 1). These premises provide a wide range of food products, pet accessories and related items but also offer grooming, boarding and dogtraining along with meeting and lecture rooms which are used, amongst other groups, by a leading provider of Veterinary Nurse training. In the Veterinary Clinic work up protocols and pricing are rigidly controlled by the management. As yet, the writer is not aware of plans for further similar sites. NEW MODELS Large Group Practices Various alternatives of practice ownership and management have developed. There are some large groups of practices under single veterinary ownership with multiple premises and many employed veterinary surgeons. Such groups exist mostly in areas of dense population. Many of these large groups, and even some under single ownership, have incorporated as ‘limited companies’ for taxation purposes. (There are lower tax rates on Companies than on individuals plus other fiscal and legal advantages) Vaccination and Neutering Clinics There is a small number of practices, usually in areas of dense population, which style themselves as Vaccination and Neutering Clinics. These offer basic services in, as the name The ‘One stop concept’ – all Petcare onder one roof A company which owns 400 premises in the United States has opened two sites in the north of England Picture 1: The One stop Pet care resort suggests, vaccination and neutering, plus microchipping and worm and flea control, often at prices lower than at conventional practices. (Picture 2). They do not offer any general veterinary treatment, clients being directed to neighbouring onventional practices for this pupose. In general, these neighbouring 102 F. J. MARSHALL EJCAP - Vol. 16 - Issue 1 - April 2006 CORPORATE GROUPS practices also have to provide any necessary emergency treatment for post-surgical complications. In the UK there are two main companies operating as corporate groups. One was started by a veterinary surgeon, the other by people with great experience of the veterinary profession through working in the pharmaceutical industry. Each obtained finance through venture capital and gradually purchased new practices as existing owners sought to sell. In some cases the sale was prompted by the inability of the vendor to find other veterinary surgeons willing to take on the responsibity of practice ownership. Relationships with such neighbouring conventional practices can be troubled but in most cases initial resentment has soon settled. The main claim of such clinics is that they encourage responsible ownership by increasing the numbers of vaccinated animals and decreasing the pool of unwanted puppies and kittens without competing with conventional practices for mainstream veterinary services. The clinic shown in picture 1 is owned by a group with several conventional clinics within a ten-kilometre radius so it can provide its own out-of-hours service. In each case the practice continues to operate under its previous identity and is reponsible for local management, working to agreed budgets for both income and expenditure and with specific profit targets. The clinical director in each practice reports to managers who take overall responsibility for a number of practices and who may, or may not, be either veterinary surgeons or other directors of the company. Out of hours clinics Out of hours services in many areas of the country are now provided by specialist clinics, some of them operating from purpose-built premises and others using premises occupied during the day by conventional practices. Some of these out of hours clinics are owned by existing practitioners whilst others are groups under the ownership of companies set up specifically for the purpose (Picture 3). The central office takes decisions on company policy in relation to suppliers of pharmaceuticals, IT services, stationery etc. It also supplies support services in matters of human resources, discipline, payroll management, payments to suppliers, VAT(TVA/IVA) etc. A committee comprising a number of clinical directors agrees policy towards choice of pharmaceuticals, diet products and other supplies. The central office then negotiates best rates with suppliers in order to maximise profit margins. Two additional but especially important new models of ownership are gradually spreading throughout the UK. These are corporate groups and joint-venture partnerships. As stated above, veterinary surgeons are seldom trained in business practices and each of these new models removes the responsibility for business management from the veterinary surgeon, allowing them to concentrate on doing what they do best – to be a veterinary surgeon. Because the practices which have been purchased have mostly been well-established multi-vet practices there has been little evidence to clients of any change, especially when the former owners have remained working in the practice to ensure continuity. This continuity has also been facilitated by the premises remaining as they were, without changes being made to show the transfer of ownership. Thus branding of the group is usually evident only on stationery and on client-related items Picture 4:‘There is no evidence that the practice is part of a Corporate Group’ 103 Patterns in Practice ownership: a UK perspective Picture 5:‘There is a stong branding of design and décor’ initial financial outlay than is likely to be required by those choosing to ‘put up their plate’* or to buy a share in an existing partnership. In addition, anyone choosing to start a new practice has to take the risk that the location chosen may not be ideal, whereas , in the case of JVP’s the company chooses sites only after extensive research into the demographics of the proposed location. such as vaccination certificates. Picture 4. shows such a practice where there is no evidence on the frontage that it is one of more than thirty premises around Britain owned by the same company. Virtually all these JVP practices are new. In consequence they tend to have only one or two veterinary surgeons initially although some have now been established long enough to become multi-vet practices. One of the groups operates from stand alone premises, sometimes adaptations of existing buildings but in other cases using newly-built commercial premises (Picture 5). The other group has several veterinary surgeries within pet superstores on large retail parks and, in addition, a few stand alone sites. JOINT-VENTURE PARTNERSHIPS As with the corporate groups, in the UK there are two main joint-venture partnership groups. In contrast to the former, however, there is a strong branding which extends from décor of premises to stationery to uniforms and even to special promotional offers. Picture 5 shows two separate premises of one of the groups and the strong branding can be seen in direct contrast to the premises in Picture 4. Each group seeks to capture clients from the existing client base of other practices by offering a more personalised approach (easy when you are the only veterinary surgeon in a clinic and thus the only one the client ever sees), and also by offering a more comprehensive service. Special offers are made in order to encourage clients to move from other practices. Many existing practices have been resentful of the opening of JVP practices in their areas but there is evidence that market extension occurs, as with the limited service clinics, with clients who had never previously visited a veterinary practice beginning to do so and free to transfer their patronage to those existing practices. Ownership of the practice is, as the term Joint-Venture Partnership (JVP) suggests, jointly between the company and the partner or partners who manage the practice. The company seeks sites which it then equips so that the practice is presented to the partners in a key in hand situation. The partners introduce capital which entitles them to work in the practice but also have a certain amount of debt towards the company. The aim is that this debt is repaid over a period of time out of the retained profits of the partner(s). CONCLUSION As with the corporately-owned practices, management aspects are organised centrally. Only individual promotional decisions are be taken locally, often with central control over policy even when budgetary aspects relate to the local practice. A number of promotional offers are determined centrally are valid in any practice in the group. The central company is paid a percentage of practice profit for these management services and the JVP retains the remainder after redemption of the initial loan from the company. Many different new types of practice have been descibed above. The most significant are the final two viz. corporate groups and joint-venture partnerships. These two emergent styles of practice are growing but do not have the momentum which might suggest that they will entirely replace the older patterns. In particular it remains to be seen how long Joint-Venture Partners will remain within such JVP arrangements rather than opting to establish their own independant practices without the need to pay part of their profit for a centralised management service. The main attraction of a JVP practice to the young veterinary surgeon is the opportunity to own a practice with much lower *start a practice totally independantly. 104 BOOK REVIEWS opinion. Finally there are significant differences between the colour reproduction of the haematology pictures that was probably not apparent in the original smears. I would recommend this book as a colour atlas of the diagnosis of diseases of falcons. However it would not be a good choice if a veterinarian wanted a single book for treating birds of prey: look at the book before you buy it. Colour Atlas of Falcon Medicine Renate Wernery, Ulrich Wernery, Jörg Kinne and Jaime Samour Published by Schlütersche, (www.schhlueterche.de) 144 pages, 378 illustrations, Hardback, ISBN 3-89993-007-X €94, £76 Dr. N. H. Harcourt Brown (UK) Ear, Nose, Throat and Tracheobronchial Diseases in Dogs and Cats. The title ‘A colour atlas of falcon medicine’ gives a guide to the contents of this book. The vast majority of the book is about a single family: Falco, although there is a small amount concerning species that these birds eat or hunt. The atlas contains a huge number of good quality pictures illustrating many aspects of falcon disease. The book is divided into several sections: Falcons and falconry in the Middle East; haematology and blood biochemistry; then viral, bacterial fungal and parasitic diseases followed by two sections concerned with miscellaneous and unknown diseases. Lastly there is a section about vaccination of these birds which has been used in an attempt to prevent a number of serious diseases. The falconry section is an interesting overview of falconry in the Middle East. It is not quite the same as falconry in Europe especially regarding the use of live pigeons to ‘train’ the falcons to kill their prey. The haematology section will prove extremely useful to anyone wishing to learn about or carrying out falcon haematology. Much of the information can be extrapolated to other avian genera. There is useful information for novices about blood collection and blood film preparation techniques. There is a description of automated counting systems that explains the pitfalls of these techniques. There are a lot of useful tables of normal falcon haematology values which are followed by many excellent pictures of the normal and abnormal blood cells. This is complemented by sections on abnormal haematology throughout the rest of the book. A similar approach is made with blood biochemistry. This section would certainly encourage clinicians to examine blood smears, a procedure which every avian veterinarian should perform. The rest of the book is devoted to the diseases seen in falcons in the Middle East, which are shown as clinical cases, gross post-mortem specimens, and as histology slides. Worm eggs and blood parasites are all well illustrated This is a most interesting book that will be of great use to anyone that has to deal with a significant number of falcons (Falco spp.). Veterinarians and technicians studying for further qualifications would also find this atlas helpful. However I think that there is a downside: although the book is entitled ‘falcon medicine’ there is no discussion of treatment or prognosis of the conditions illustrated. Another complaint is that there are many useful and interesting comments that would have been even more valuable if they were referenced. It is difficult for the reader to know what is fact and what is Anjop Venker van Haagen Published by Schlütersche, ( www.schluetersche.de) 248 pages, 182 illustrations, Hardback, ISBN 3-87706-635-6 €89, £71 Ear, Nose and Throat symptoms are common among the clinical problems found in the daily caseload of veterinary surgeons dealing with companion animals. Inflammatory, degenerative and neoplastic diseases are common diagnoses. Although the symptoms may be very easy to detect, it is often very difficult however to reach a proper evaluation of the problem and reach a precise final diagnosis. In fact to achieve this, a detailed knowledge of the anatomy and the physiopathology is required and this has to be supported by adequate equipment and diagnostic techniques. This book provides precise and detailed information concerning the anatomy, the functions, and the way to approach the physical examination. It continues with the diagnostic techniques, the classification of the disease, the differential diagnosis and eventually the correct treatment of each case. An ENT workup is usually a complex mixture of both clinical and surgical approaches and a good knowledge of both these aspects of the patient is necessary. The book is divided into six sections covering the ear, the nose and nasal sinuses, the pharynx, the larynx, the trachea and bronchi and ending with an interesting chapter on cranial neuralgias and paralysis. The pictures, tables and drawings are presented in an exquisite way, being detailed, perfectly printed and easy to interpret. Every topic is comprehensively covered with pictures detailing clinical signs, diagnostic imaging examples and histopathology features. It is a book that will help both the student in the study of these diseases and the experienced practitioner in approaching cases which are difficult to treat. The high level of experience of the author, an internationally recognised authority in this field for many years, guarantees the quality of the information contained in this book. Dr Venker van Haagen also chairs the Scienific Advisory Committee of the World Small Animal Veterinary Association (WSAVA). Dr. Claudio Brovida (I) 106 BOOK REVIEWS My overall impression is of a useful and accessible guide with up to date information on canine and feline behaviour problems; extended with features like ‘summary textboxes’ and ‘immediate action’ boxes that provide key information for problem cases and behavioural emergencies. To conclude, this book will be a helpful tool in everyday practice and is highly recommended for veterinary practices with interest in behaviour. Dr. Tiny De Keuster (B) Behaviour problems in small animals – Practical advice for the veterinary team Jon Bowen and Sarah Heath. . Published by Elsevier Saunders, (http://intl.elsevierhealth.com.vet) 283 pages, Paperback (2005), ISBN 0702027677 €39,95, £26.99 Notes on rabbit internal medicine This book is an excellent and practical guide for the veterinary practitioner. The content covers behaviour problems in cats and dogs, and is divided into 4 Parts and 16 Chapters. Part one contains a range of practice tips on how to provide a behavioural service as well as preventive behavioural care such as how to run puppy & kitten classes. Part two contains the basic tools used in behavioural medicine: an introduction to canine and feline social behaviour and communication, followed by an excellent chapter on learning theory and behaviour modification. In the next chapter the authors clarify the role of pharmacology in behavioural medicine: the classes of psychoactive drugs, management of drug therapy, case selection, monitoring and the termination of treatment, are tackled in a comprehensive way. I was particulary pleased to see that the authors repeatedly explain the limitations and pitfalls of drug therapy, for example that drugs are not a substitute for a behavioural work up. The last chapter of part two describes the management of ageing dogs and cats, the diagnostic tools to recognize cognitive impairment and dementia, as well as treatment and prognosis options. Part three covers canine behavioural problems: canine fear, anxiety and phobia related disorders, canine compulsive disorders, canine elimination problems and canine aggression problems. Part four covers feline behavioural problems: feline fear, anxiety and phobia; feline compulsive disorders, feline house soiling, marking and feline aggression problems. Each of these chapters take into consideration the physiological and neurochemical underlying mechanisms, diagnosis, prognosis, summary of treatment methods as well as comprehensive counselling advice. On top of the excellent guidelines on behavioural problem solving, the book is illustrated with beautiful drawings and pictures. The book concludes with suggestions for further reading which is unfortunately quite short, and appendices containing referral forms and very useful cat and dog handouts. However, a few minor shortcomings of this book need to be mentioned. In the preface the authors explain the reason why no references at all are cited in the text (to keep it readable). In my opinion, the book would benefit from adding scientific references in order to allow the practitioner to read more in depth and to clarify the origin of provided information. Further, there are some discrepancies between the information provided in different chapters (chapter 6 and 8) concerning the indication of SSRI’s in canine aggression and the SSRI’s anticholinergic side effects. Richard Saunders and Ron Rees Davies Blackwell Publishing Ltd. (www.blackwellpublishing.com) 240 pages, Paperbck (2005), ISBN 1405115149 € 44 (approx), £29.99 Rabbits are the third most popular animal kept as pets, and in recent years both the interest from veterinary surgeons and the expectations of rabbit owners has increased considerably. A number of texts on rabbits have been published, either as a section within a book or as a book devoted completely to rabbits. However whilst some of these books have been excellent there has been little attempt to approach rabbit medicine from the point of view of differential diagnoses, which this book does. It leads the reader through the possibilities for various clinical signs in a systematic way, rather than taking an individual disease approach. It is written in note form, which helps to make the information readily available, and is therefore intended as an accessible reference text. As well as the section on differential diagnoses, there is a major section on organ systems, which complements this approach. This section includes information on the feeding and nutrition of rabbits, as well as listing the causes of disease, clinical signs and treatment within each organ system. In addition there is a comprehensive section on laboratory findings, with lists of conditions that cause an alteration in the normal parameters of blood cells and biochemistry. The small section on therapeutics concentrates on the areas of treatment that differ from the more common species in small animal practice. Some diseases, especially infectious ones, do not readily fall within a single organ system, and these receive individual attention in a separate section of this book. There is an extensive bibliography that will allow additional information to be found if required. A thorough contents and index are helpful in locating the information contained within these notes, although it is all laid out in a logical way. This book would certainly find a useful place in any practice treating rabbits, although being a medicine text it may need to be complemented by other information sources for anaesthesia and surgery. Dr. Owen Davies (UK) 107 BOOK REVIEWS up-most quality and in black and white, which allows the reader to interpret them with his/her own colour references, depending of the laboratory techniques and nuances. Last but not least the most appropriate references are listed at the end of each subchapter. The second part of the book describes in detail all the epithelial and mesenchymal neoplasms of the skin (in 5 and 11 subchapters respectively). The classification and terminology are based on World Health Organization standards. Clinical and histopathological characteristics of tumours are described, often with a comparison of their human counterpart. There are beautiful histopathological illustrations in black and white and in colour for immunohistochemical stainings, indispensable in many instances. Most appropriate references appear at the end of each subchapter. This book offers a magnificent clinical and histopathological description of all the non-neoplastic skin diseases and neoplastic skin tumours of dogs and cats known at the beginning of the 21st century! Furthermore it gives additional information on pathogenesis, epidemiology, and comparative dermatology and dermatopathology. The 944 page text is exhaustive, perfectly written and in total there are 1250 superb clinical and histopathological illustrations. Diagnosis is an art in both dermatology and dermatopathology, a discipline by itself. When biopsies are done, this art establishes the link between clinical signs and microscopic signs through the indispensable “anatomo-clinical relation”. This book is all about it. Charles Leblois (1892-1955), the founder of the French School of veterinary dermatology, wrote in 1926 “Diagnosis is an art I pursue with passion”*. There is no doubt that the authors also have this deep passion! Indeed, every general practitioner interested in dermatology, every histopathologist interested in the skin and a fortiori every dermatologist and dermatopathologist should have this book, a masterpiece, permanently to hand. Skin Diseases of the Dog and Cat Clinical and histopathologic diagnosis- Second edition. Thelma Lee Gross, Peter J. Ihrke, Emily J. Walder, Verena K. Affolter. Blackwell Publishing Ltd. (www.blackwellpublishing.com) 944 pages, Hardback (2005), ISBN: 0632064528, €215, £149.50, Approx This is the second edition of what is already a remarkable work, i.e. the first edition published in 1992 by the first 3 authors. The first impression is as follows: this is a big heavy book, with a good hard cover; you do not have in your hand another small dermatology manual or colour atlas. In addition the quality of the paper is extremely good and the layout is very nice. This renders the book easily readable, i.e. to be open for studying as well as when you need it in a particular clinical situation. Furthermore, the contents at the front and index at the back are both highly comprehensive. The first part covers inflammatory, dysplastic and degenerative diseases, and is divided in chapters about the epidermis, the dermis, the adnexa and the panniculus. In each chapter, patterns are envisaged systematically in subchapters: 8 for the epidermis, 7 for the dermis, 5 for the adnexa, 1 for the panniculus. This is a morphological classification. For all the diseases however, the authors have put together the pathogenesis, predilections, clinical features including updated nomenclature, comparison to human diseases, and cutaneous histopathology of these diseases, including biopsy site selection. Inevitably, some diseases are divided in two chapters e. g. pemphigus foliaceous, discoid lupus erythematosus, feline eosinophilic plaque and ulcer, dermatomyositis, etc, but this had to be expected as many diseases affect several components of the cutaneous tissue. Clinical pictures, all in colour, illustrate ideally the typical aspects of the diseases. Histopathological pictures are of the *‘Diagnostiquer est un art que je sers avec passion’, in ‘DOCUMENTS pour servir à l’Edification d’une DERMATOLOGIE ANIMALE (Chien et Chat)’ Vigot Frères, Paris, 1926 Dr. Didier-Noel Carlotti Dip ECVD (F) 108 BOOK REVIEWS veterinary practice such as “Demodex canis is a prostigmatid mite” (“prostigmatid” describes a subclass of mites) contribute to the enormous volume covered. The reader may thus get the impression that the book was composed for veterinary practitioners and students instead of veterinary nurses and technicians. The first edition has still a number of errors, such as in spelling (e.g. “Demodex follicuarium” instead of the correct term “Demodex folliculorum”) or in a figure where the reader has to understand that A, B, C in the text corresponds to 1, 2 and 3 in the drawing. The light microscope expandeded for a better perception of its parts shows among others a reflecting mirror. Today such types of microscopes are usually found in museums and are not used in practice. Taken as a whole, the manual is very promising. It is hoped that the second edition will correct the errors. Veterinary Dermatology A manual for nurses and technicians Francis Gaudiano, Cathy Curtis Published by Elsevier Saunders (http://intl.elsevierhealth.com.vet) 241 pages, Paperback. ISBN 0750 8804 1, €39,95, £26.99, Skin problems are the most common disorders seen by veterinarians in small animal practice. Veterinary nurses and technicians are regularly involved in the management of dermatological conditions including diagnostic and therapeutic procedures. A manual on veterinary dermatology for nurses and technicians has been needed for a long time as a source of reference and as a guide to nurses and technicians entering the field of dermatology. This book is published in paperback binding and has 241 pages. After an overview on the structure and function of the skin 12 chapters cover dermatology clinics, diagnostic tests, skin diseases caused by ectoparasites, bacteria and fungi, skin allergies, endocrine, metabolic and paraneoplastic disorders, keratinisation and pigmentation disorders, ear diseases, autoimmune skin diseases, tumours, wounds, and dermatological conditions in exotic pets (13 chapters in total). The chapters are well structured and the text is overall easy to read. Glossaries of terms and case studies are very helpful in the understanding of complex contents. Exceedingly rare skin diseases such as Lichenoid psoriasis in English Springer Spaniels and information beyond the normal scope of daily Hans-Joachim Koch Dip ECVD (D) VÖK CONTINUING EDUCATION SEMINARS 2006 INDEX OF ADVERTISERS Company Page AFFINITY PETCARE................ 7 AVID ..................................... 99 BLACKWELL PUBLISHING ..108 CSAVA/FECAVA/ESFM ........ 50 CPD SOLUTIONS ................105 DATAMARS .......................... 94 ECVIM-CA.............................. 20 ELSEVIER SCIENCE ............. 109 ESFM..Inserts in some countries ESVOT ................................... 49 EVDS ................................... 72 HELAPET ............................. 62 Advertorial ............................. 62 HILL’S PET NURTITION............. Inside front Cover and page 26 Company All to be held in Austria in the German Language Page 22 - 23 April Seminar on Practice Management/ Marketing “Optimization of the Veterinary Practice” 20 - 21 May Vienna Seminar „Clinical Update for Practising Vets - From Practitioners for Practitioners“ 27 May Steyr VÖK Intensive Seminars on 03 June ULTRASOUND. Each Seminar has a 30 September maximum number of 10 participants – 07 October Early reservation essential! 06 June Vienna 13th ROYAL CANIN/Waltham® Seminar on DIETETICS Gastrointestinal diseases in the dog and cat” 28 – 29 Oct. Vienna VÖK Seminar on ONCOLOGY (Part 1) 04-05 Nov. Vienna Seminar on Practice Management/ Marketing “Optimization of the Veterinary Practice” 11- 12 Nov. Steyr 19th VÖK Seminar on ULTRASOUND “Abdomen – Special Cases” 25 - 26 Nov. Krems 31st VÖK Seminar on X-RAY 04- 05 March Salzburg Bavarian Ethological Seminars “Dog 01- 02 April education and behaviour”. Reduced fee 13- 14 May for VÖK and VTÖ members For further information visit: www.voek.at or contact: [email protected] IAMS EUKANUBA .................. 4 IMEX .....................................32 INTERVET ............................ 3 KRUUSE ............................... 71 LIFELEARN ........................... 72 MERIAL....... Inside back Cover FECAVA/WSAVA/CSAVA....... 6 ROYAL CANIN /WALTHAM ...... .................................Back cover SVK /ASMPA ..................... 100 SHOR-LINE .........................105 TECKNIK TECHNOLOGY .. 31 WOODLEY EQUIPMENT ...... 9 109 Wels CALENDAR OF MAIN EUROPEAN NATIONAL MEETINGS AND OTHER CONTINUING EDUCATION OPPORTUNITIES A list of the addresses and telephone numbers of the Secretariat or person holding information is attached. WSAVA & FECAVA Congresses (Red) National meetings (blue) 2006 8-9 April 19-22 April 20-23 April 22-23 April AIVPA-FE NACAM BSAVA AVEPA Pisa Amsterdam Birmingham Seville Mallorca Las Palmas Cremona Scivac HQ Verona Zaragoza Gijón Tallinn 2-5 May SCIVAC 7 May 13-14 May AIVPA AVEPA 13-14 May ESAVA 18-20 May 19-20 May 19-21 May 20-21 May 20-21 May SVK/ASMPA SCIVAC AFVAC/GEDAC AVEPA AIVPA-FE 20-21 May 8-10 June 29 June -1 July 7-9 September 7-10 September 14-16 September 16-17 September 21 September 22 September 23-24 September SAVAB ESVD ECVS ESVD-ECVD ESVOT ECVIM-CA VÖK ECVBM-CA ESVCE WDWE 21-24 September 23-24 September GSAVA AVEPA 7-8 October AIVPA 11-14 October 27-29 October 21-22 October 3-5 November 9 - 10 November 10-11 November 10-11 November 18-19 November 19 November 23-24 November 25-26 November FECAVA/WSAVA/ CSAVA AVEPA AIVPA-FE SCIVAC SSAVA DSAVA TSAVA AVEPA AIVPA-FE AVEPA AVEPA 3 December 7-9 Dec AIVPA AFVAC CE course “Feline Radiology” Voorjaarsdagen Annual Congress CE Ophthalmology CE Trauma CE Neurology Practical Course on Rehabilitative Physiotherapy in dogs Round Table “Psycho-physical Stress in working dogs” CE Oncology CE Cardiology Annual Congress Ear, nose, throat diseases-FECAVA supported CE Interlaken Annual Congress Rimini 52nd SCIVAC Congress Paris (F) Annual Congress Santiago CE Trauma Parma CE course “Feline Ultrasonography and Echography” Theory and practice Antwerp Zoonotic diseases Spa (B) Workshop (Dermato-endocrinology) Sevilla (E) 15th Annual Scientific Meeting Lisbon (P) Annual Congress Munich(D) Annual Congress Amsterdam Annual Congress Salzburg 21st.Annual-Meeting “Ear, Nose and Throat” Ghent(B) Current research in behaviour and welfare Ghent(B) Welfare and Behaviour: The Science behind the Art Ghent(B) 10th Anniversary Conference of the Flemish Working Group on Ethology # Welfare and behaviour: the science behind the art) Dusseldorf 52 Annual Congress Alicante CE Trauma Mallorca CE Ophthalmology Modena National Congress “Gastroenterology surgery updating” Prague 12th FECAVA/30th WSAVA/CSAVA Congress Madrid National congress Perugia CE “Cats and dogs Haematology and Cytology” Perugia 53rd SCIVAC Congress Uppsala Annual meeting Aarhus Annual Congress Istanbul 1st Anadolum Congress Barcelona CE Oncology Messina Study Day “Feline Dermatology” Sevilla CE Trauma Madrid CE Oncology Bilbao CE Cardiology Las Palmas CE Emergency Care Agnano (Napoli) Seminar “Endocrinology” Bordeaux Annual Congress 28 March- 1 April FECAVA/CSAVS Dubrovnik ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ Italian Dutch, English & Others English * Spanish Spanish Spanish English / Italian Italian Spanish Spanish English German/French/English Italian, English French Spanish Italian Dutch English English English English English German, English English English English German Spanish Spanish Italian, English English & Others Spanish, English Italian Italian, English Swedish English/Danish English, Turkish Spanish Italian Spanish Spanish Spanish Spanish Italian French 2007 13-17 April 27-29 April 3-5 May 26-27 May 26-29 August 19-20 October Last Weekend November BSAVA NACAM SVK/ASMPA SAVAB WSAVA AVEPA Birmingham Amsterdam Montreux Antwerp Sydney (Aust) AFVAC FECAVA/CSAVS/ESFM European Congress Annual Congress Voorjaarsdagen Annual Congress Obesity Seminar World Congress National Congress ★ ★ ★ ★ ★ ★ ★ ★ Annual Congress * 60 Veterinary surgeons or 70 Nurse Registrants are required for simultaneous translation to be provided # WDWE Contact: www.behaviour2006ghent.be 110 English and others ★ ★ ★ ★ English* Dutch English and others German French and English English Dutch English and others Spanish English French BSAVA CONTINUING EDUCATION COURSES 2006 All to be held in the UK, in the English Language. When at Gloucester in the BSAVA HQ 11th May Warrington Which Bag Do I Chose? Fluid Therapy and Transfusion Medicine 30th May Hinckley Feline Modular - Looking through cats eyes: feline ophthalmology made easy 31st May Gloucester Small Animal Medicine Modular - Endocrinology II 10th - 11th June Beaconsfield Challenges in Emergency Medicine and Critical Care (Medical Bias) 16th-17th June Oxford Critical Care and Emergency Surgery - Check Your Own Pulse First 19th-20th June Bromsgrove Urinary Tract Surgery: Can’t Go, Won’t Stop: Regulating The Flow 22nd June Gloucester "Disorders of the South End of the Dog – Some Surgical Solutions" 27th June Hinckley Feline Modular - The Jaundiced Cat 28th June Gloucester Small Animal Medicine Modular - Cancer: Presentation to Palliation 2nd-3rd September Buxton Spinal Surgery oops! 5th September Knutsford Brain cases ? Intracranial localisation makes my head hurt! 7th September Leicester "Image is everything, Darling!" 13th - 14th September Beaconsfield Amazons to zebra finches: A modern, practitioner approach to exotic avian medicine 28th September Warrington This pet has travelled abroad - the risk of exposure to exotic infectious agents 30th Sept -1st Oct Melton Mowbray The Beginners Guide to Small Animal Diagnostic Ultrasonography 3rd October Gloucester Therapeutics Modular - Antimicrobial and Fluid Therapy 4th October Gloucester Small Animal Medicine Modular - Upper Urinary Tract 5th October Gloucester Small Animal Medicine Modular - Lower Urinary Tract 7th November Gloucester Therapeutics Modular - Analgesia 8th November Gloucester Small Animal Medicine Modular - Antimicrobial Therapeutics 9th November Basingstoke A cavity with a view - Advances in endoscopic surgery 10th November Basingstoke Wounds That Make Your Skin Crawl 13th November Kettering Understanding Joint Disease 14th November Kettering Fixing the Fractured Feline 5th December Gloucester Therapeutics Modular - Cytotoxics and Chemotherapeutics 6th December Gloucester Therapeutics Modular - Cardiovascular Therapeutics For Information visit: www.bsava.com or contact: [email protected] ESAVS CONTINTUING EDUCATION COURSES 2006 All courses to be held in the English language. Advanced Veterinary Studies 11 - 15 September 2 - 7 October 19 - 24 June 24 July - 4 August 7 - 18 August 5 - 9 July 10 - 14 July 10 - 14 July 13 - 17 September 4 - 8 September 13 - 24 November 21 - 25 October 30 September - 4 October 14 - 18 October 28 August - 8 September 26 June - 1 July 10 - 15 September Milano / Italy Salzburg / Austria Luxembourg Vienna / Austria Vienna / Austria Berne / Switzerland Berne / Switzerland Brno / Czech Republic Brno / Czech Republic Zurich / Switzerland Utrecht / Netherlands Berne / Switzerland Berne / Switzerland Berne / Switzerland London / United Kingdom Luxembourg Zurich / Switzerland Behavioural Medicine II Cardiology III / Advanced Cardiology Dentistry II Dermatology I Dermatology II Diagnostic Ultrasound I Emergency Care I Endoscopy Intensive Course Exotic Pets Medicine & Surgery Feline Medicine & Surgery II Internal Medicine II Neurology I, Neurology II Neurology III / Advanced Neurology / Neurosurgery Ophthalmology I Oral Surgery Small Animal Reproduction II Excellence in Veterinary Therapy 1 - 5 November Palma de Mallorca / Spain 24 - 28 April Shanghai / China Small Animal Therapy: Cardiology and Orthopaedics Optimizing the Management of Clinical Disorders in Companion Animals: Internal Medicine and Emergency Care For Information visit: www.esavs.org ADVANCE NOTICE 2007 2008 2009 BSAVA 13 – 17 April Voorjaarsdagen 27-29 April FECAVA/CSAVS 30/3-1/4 Voorjaarsdagen 24-26 April AFVAC Last weekend November Voorjaarsdagen 23-25 April SVK/ASMPA 22-24 May (Interlaken) WSAVA 26 – 29 August(Sydney Aust.) AVEPA 19 – 20 October BSAVA 3-6 April BSAVA 2-5 April 111 AFVAC Last weekend November FECAVA/WSAVA/ VICAS 23-26 August SECRETARIAT OR ADDRESS TO CONTACT FOR INFORMATION (Full Association names are given at the front of the Journal) AFVAC/ CNVSPA AIVPA APMVEAC AVEPA BASAV BHSAVA BSAVA CSAVA CSAVS DSAVA ESAVA FAVP GSAVA HSAVA HVMS LAK LSAPS LSAVA MSAVA MVA NACAM NSAVA PSAVA RSAVA SAVAB Secretariat: 40 rue de Berri – F-75008 Paris Tel: (33) 1 53 83 91 60 – Fax: (33) 1 53 83 91 69 E-mail: [email protected] Contact: Dr Giuseppe Tranchese Via G. Marconi 107 - I-800030 I-800030 Mariglianella (Naples) Italy E-mail: [email protected] Website: www.seltravet.it Tel: (39) 081 8856776 – Fax: (39) 081 8856622 Contact: Dr. Vieira Lopes Rua Américo Durao No 18-D/as Olaias P-1900 Lisboa Tel: (351) 1 840 41 79 – fax: (351) 1 840 41 80 E-mail: [email protected] Secretariat: Paseo San Gervasio 46-48, E7 E-08022 Barcelona Tel: (34) 93 2531522 – Fax: (34) 93 4183979 www. avepa.es Director: Dr. Boyko Georgiev Tzarigradsko shausse 73 Sofia 1113, Bulgaria Tel: (359) 88 927160 – Fax: (359) 66 44 50 E-mail: [email protected] Contact: Dr. Josip Krasni-Alipasina St. 37 7100 Sarajeva – Bosnia and Herzegovina E-mail: [email protected] Secretariat: Woodrow House 1 Telford Way, Waterwells Business Park Quedgeley, Gloucester GB-GL2 4AB Tel: (44) 1452 726700 – Fax: (44) 1452 726701 www.bsava.com Contact: Dr. Jiri Beranek University of Veterinary and Pharmaceutical Sciences – Palackého 1/3 – 612 Brno Czech Republic Tel: (420) 603 272 796 – Fax: (420) 549246974 * E-mail: MED.PROD@worldonline .cz Contact: Dr. Davorin Lukman Specijalizirana Ambulanta Varazdin Trnovecka 6, 42000 Varazdin, Croatia Tel/Fax: (385) 42 331 895 E-mail: [email protected] Secretariat: Emdrupvej 28 A, DK 2100 Copenhagen Tel: (45) 38 71 08 88 – Fax: (45) 38 71 03 22 E-mail: [email protected] Contact: Dr. Tiina Toomet Kopli 4A Tallinn, EE-0004 Estonia Tel: (372) 6413 11 – Fax: (372) 641 3110 E-mail: [email protected] Contact: Dr. Kaj Sittnikow Ykskoivuntie 32, FIN-23500 Uusikaupunki Tel: (358) 2 844 2580 Fax: (358) 2 844 2589 E-mail: [email protected] * Contact: Dr. Angelika Drensler Gerberstr. 26 – D-25335 – Elmshorn Tel: (49) 4121 266 369 Fax: (49) 4121 265 895 E-mail: [email protected] Contact: Dr. Zsolt Kendik Isvan u. 2 Budapest H-1078 Tel: (36) 305950750 E-mail: [email protected] Contact: Dr. Katerina Loukaki Protopapa 29, Helioupolis, GR- 163 43 Athens Tel/Fax: (30) 2109932295 E-mail: [email protected] Secretary: Tom Angel 28, rue de Syren – L-5870 Alzingen Tel: (352) 36 9807– Fax: (352) 36 9807 E-mail: [email protected] Contact: Dr. Lita Konopore Zvaigznáju Gatve 2 Riga, LV-1082 Tel: (371) 7546 366 – Fax: (371) 7606 202 E-mail: [email protected] President: Dr. Saulius Laurusevicius Tilzes 18 – LT-3022 Kaunas Tel & Fax: (370 37) 363 490 E-mail: [email protected] Contact: Dr. S. Cokrevski, Ul. Lazar Ppo Trajkov 5-7 Skopje, Fyrom Tel: (389) 91 115 125 – Fax: (389) 91 114 619 E-mail: [email protected] Contact: Dr. C.L. Vella Blue Cross Veterinary Clinic Msida Road, Birkirkera, Malta Tel: (356) 225 363 – Fax: (356) 238 105 E-mail: [email protected] Director: Dr. Leen den Otter Dorpsdijk 16 - NL - 3161 KE Rhoon Holland Tel: (31) 10 5012414 E-mail: [email protected] Contact: Kjetip Dahl PO Box 6781 St. Olavs Plass N-0130 Oslo Tel: (47) 22 994600 – Fax: (47) 22 994601 E-mail: [email protected] Contact: Dr. Jerzy Gawor UI Chlopska 2a 30-806 Kracow Tel/Fax: (48) 12 658 8365 E-mail: [email protected] Contact: Dr. A. Tkachov-Kuzmin V-Kojinoi, 23 – 121096 Moscow, Russia Tel/Fax: (7) 095 921 6376 E-mail: [email protected] Contact: Dr. J van Tilburg Ernest Claeslaan 14 B-2500 Lier Tel: (32) 3 489 2309 – Fax: (32) 3 480 1942 E-mail: [email protected] Contact: SAVAB Flanders: Dr. Leen Verhart G. Van der Lindenlaan 15 B-2570 Duffell Fax: (32) 15 31 73 90 E-mail: [email protected] SCIVAC Secretariat: Palazzo Trecchi Via Trecchi 20 – I-26100 Cremona Tel: (39) 0 372 460440 – Fax: (39) 0 372 457091 www.scivac.it SkSAVA Contact: Tibor Brauner Uhrova 1 831 01 Bratislava Slovak Republic Tel/Fax: (421) 7 54 78 80 93 E-mail: [email protected] SMASAP Director: Denis Novak Dr Ivana Ribara 186/30, 11070 Belgrade, Serbia Tel/fax: (381) 11 2851 923; (381) 11 382 17 12; (381) 11 2604 289 E- mail: [email protected] SSAVA Contact: Dr. Anne Carlswärd Jönköping Small Animal Hospital Oskarshallsgatan 6 – 8-553 03 Jönköping Tel: (46) 36 34 18 80 Fax: (46) 36 34 18 85 E-mail: [email protected] SVK/ Contact: Dr. Peter Sterchi ASMPA Mühlegrund – CH-3807 Iseltwald Tel: (33) 845 11 45 E-mail: [email protected] SZVMZ Contact: Dr. Zorko Bojan Veterinary Faculty, Gerbiceva 60, SLO-1000 Ljubljana, Slovenija Tel: (386) 14779277 – Fax: (386) 647007111 E-mail: [email protected] TSAVA Director: Prof. Mustafa Aktas University of Istanbul- Faculty of Veterinary Medecine, Dept. of surgery. Avcilar Campus. 34320-Avcilar/Istanbul-Turkey Tel: 0212-4737070/17297 – Fax: 0212-4737240 E-mail: [email protected] USAVA Contact: Dr. Vladlen Mykhaylovich USHAKOV 8 Filatova str., Apartement 24, Odessa 65000, Ukraine Tel.: (380) 503369810 Fax: (380) 482 606726 VICAS Contact: Dr. Peter A. Murphy Summerhill Veterinary Hospital, Wexford, Co. Wexford Ireland Tel: (353) 53 43185 – Fax: (353) 53 43185 by request www.veterinary-ireland.org E-mail: [email protected] VÖK Contact: Silvia Leugner Royal Canin Österreich GmBH Hietzinger Hauptstrasse 119, A-1130 Wien Tel: (43) 1879 1669 DWI8 - Fax: (43) 18791669-11 E-mail: [email protected] Associate members ESAVS ECVD ECVS ESFM ESVC ESVCE ESVD ESVIM ESVN ESVOT EVDS EVSSAR Contact: EAVS Office Birkenfeld, Schadtengasse 2 D-55765 Birkenfeld Tel: (49) 6782 980650 – Fax: (49) 6782 4314 E-mail: [email protected] Contact: Dr. Dominique Héripret Clinique Vétérinaire Frégis 43, avenue Aristide-Briand F-94110 Arcueil E-mail: [email protected] Tel: (33) 149 85 83 00 – Fax: (33) 149 85 83 01 Contact: Executive Secretary – ECVS Office Winterthurerstrasse 260, CH-8057 Zürich Tel: (41) 44 635 84 08 – Fax: (41) 44 313 03 84 E-mail: [email protected] Contact: Claire Bessant Taeselbury, Highstreet, Tisbury, Wiltshire, GB - SP3 6LD, UK Tel: (44) 1747 871872 - Fax: (44) 1747 871873 E-mail: [email protected] or [email protected] Contact: Dr. Chris Amberger 96, rue de la Servette CH-1202, Geneve E-mail: [email protected] Contact: Dr. Sarah Heath 11 Cotebrook Drive, Upton, Chester GB-CH2 1RA Tel: (44) 1244 377365 – Fax: (44) 1244 399288 E-mail: [email protected] or: [email protected] President: Chiara Noli E-mail: [email protected] E-mail: [email protected] Tel: (33) 149 85 83 00 – Fax: (33) 149 85 83 01 Contact: Prof. Jean-Pierre Cotard Ecole Nationale Vétérinaire d’Alfort 7 avenue du Général de Gaulle F-94700 Maisons-Alfort Tel: (33) 1 439 67162 – Fax: (33) 1 489 38761 www. vet.uu.nl/esvim/www.ecvimcongress.org www.ecvimcongress.org Contact: Dr. Gualtiero Gandini Dipartimento Clinico veterinario Facoltà di Medicina Veterinaria Università degli Studi di Bologna I-Via Tolara di Sopra 50 I-40064 Ozzano Emilia (Bologna) [email protected] Contact: Dr. Aldo Vezzoni, SCIVAC Palazzo Trecchi 20 – I-26100 Cremona Tel: (39) 0 372 23451 Fax: (39) 0 372 20074 www.esvot.org Contact: Dr. Margerita Gracis Piazza del Carmine 2 I-20121 Milano Tel: (39) 2 338 187 4498 – Fax: (39) 02 878 353 E-mail:: [email protected] Contact: Dr. Catherina Linde-Forsberg Department of Obstetrics and Gynaecology PO Box 7039 Swedish University of Agricultural Sciences SE – 750 07 Uppsala E-mail: [email protected]