New Directions in Diagnosis and Treatment of Canine Acute Pancreatitis

Transcription

1 1 New Directions in Diagnosis and Treatment of Canine Acute Pancreatitis Caroline S. Mansfield BSc BVMS (Murdoch), CertSAM, MANZCVS, MVM (University College, Dublin), DECVIM-CA This thesis is presented for the degree of Doctor of Philosophy of Murdoch University School of Veterinary and Biomedical Sciences November 2011

2 2 Declaration I declare that this thesis is my own account of my research unless specifically stated and contains as its main content, work which has not previously been submitted by me for a degree at any tertiary education institution. Caroline Sarah Mansfield Date: 20/11/2011

3 3 Abstract Acute pancreatitis is an important disease in companion animal medicine, and diagnostic methodology available to veterinary practitioners is often limited. Evidence based principles for the management of this common disease are also lacking. This thesis explores the current diagnostics of canine pancreatitis and management of this condition, reviewing the literature across both the veterinary and human medical fields. Assessment of the specificity of canine pancreatic-specific lipase (cpl) was made in a post-mortem study and calculated to be 82-92%, with a correlating sensitivity of 45-55%. A multi-centre study of dogs presenting with clinical signs consistent with acute pancreatitis to assess a new laboratory test, serum canine pancreatic elastase-1 (cpe-1) was also performed. This test had a sensitivity ranging from 66-79%, with a specificity of 92%. The sensitivity of both laboratory tests was greater in dogs with severe disease. To assess potential treatment options, a clinical severity score was established, with gut health, respiratory complications, cardiac complications, and blood pressure determining the final score. Retrospectively, plasma administration did not appear to be associated with treatment success, but this conclusion was limited by the retrospective nature of the study and small numbers of dogs. Out of the other factors, fasting for 3 or more days was the one most significantly associated with mortality. To begin assessment of nutritional modalities, pancreatic responses in healthy dogs to varying dietary fat composition (ranging from 4%DW to 16% DW) was assessed, with no statistical difference determined. On the basis of this, a pilot study of 10 dogs with severe pancreatitis was undertaken, with 5 dogs fed enterally and another 5 dogs were given total parenteral nutrition (TPN). No differences in mortality or days of hospitalisation between the two were found, but there were significantly less episodes of vomiting or regurgitation in the dogs given food (p < 0.001). There were also more

4 4 severe complications (4/5) in the TPN group compared to the enteral feeding group (2/5). In all, this thesis supports the new premise of enteral feeding of dogs with acute pancreatitis early in the course of disease, determines the sensitivity and specificity of two diagnostic tests and has established an objective marker of disease severity.

5 5 Acknowledgements Studies within this thesis were supported by the European College of Veterinary Internal Medicine Clinical Studies Fund; Early Career Researcher Funds, Murdoch University; and Nestle Purina PetCare company. Laboratory assistance was provided by Murdoch University Clinical Pathology laboratory, Royal Perth Hospital, ScheBo Biotech Germany and The GI Laboratory, Texas A & M University. Kate Patterson, MediPics and Prose assisted with medical illustrations. I am extremely grateful for the collaboration of co-authors in these studies and the assistance of nursing, veterinary and technical staff at Murdoch University. I would also like to thank my mentors at various stages of my clinical and research career: Boyd Jones at University College, Dublin; John Pluske at Murdoch University; and Ted Whittem at the University of Melbourne for allowing me to complete this project. My supervisors Professors Ian Robertson and Jacqueline Phillips were invaluable in their support and analysis of this thesis, and I thank them for this. Finally, but most importantly, I would like to thank my wonderful family for their forbearance and patience. Gary, Alannah, Zoe and Cooper- this is the last time (I promise)!

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7 Table of Contents: Introduction Purpose List of abbreviations Chapter 1: Literature Review Normal anatomy and physiology of the canine pancreas Normal Canine Pancreatic Anatomy Normal pancreatic physiology Pancreatitis: The Disease Animal experimental models Pathophysiology of pancreatitis Classification of pancreatitis Aetiology and risk factors in dogs Prevalence and mortality rates in dogs Clinical signs Complications Pancreatitis: The Diagnosis Differential diagnosis Routine clinical pathology Specific biochemical assessment Canine Pancreatic Lipase Serum Pancreatic Elastase Diagnostic Imaging Histopathology Assessing severity Pancreatitis: Treatment Intravenous (IV) fluid therapy Plasma Anti-emetics Antibiotics Analgesia Gastric acid suppression Treatment of complications New therapeutic directions Anti-inflammatory therapy Follow-up management Nutrition Conclusions from the literature

8 1.6 Hypotheses Aims and objectives Chapter 2: Specificity and sensitivity of serum canine pancreatic elastase-1 concentration in the diagnosis of pancreatitis Introduction Materials and Methods Animal Selection Assays Statistical analysis Results Animal Information Median and intervals Sensitivity and specificity cpe Discussion Conclusion Chapter 3: Association between canine specific pancreatic lipase (Spec-cPL ) and histological exocrine pancreatic inflammation in dogs: assessing specificity Introduction Materials and Methods Results Discussion Conclusion Chapter 4: Development of a clinical severity index for dogs with acute pancreatitis Introduction Materials and Methods Inclusion criteria Development of the severity scoring index Serum CRP concentration measurement Statistical analysis Results Animals Clinical severity index and organ scoring scheme Assessment of serum CRP concentration Discussion Conclusion Chapter 5: Retrospective analysis of the effect of plasma and microenteral nutrition administration on mortality and morbidity in dogs with acute pancreatitis Introduction Materials and Methods

9 5.2.1 Animal selection Data collection Statistical Analysis Results Discussion Conclusion Chapter 6: Pancreatic response in healthy dogs fed diets of various fat compositions Introduction Materials and Methods Analytical validation of an assay for gastrin Study protocol Data analysis Results Dogs Serum sample quality Gastrin assay validation Serum ctli concentration Serum cpli concentration Serum gastrin concentration Data comparisons Discussion Conclusion Chapter 7: A pilot study to assess tolerability of early enteral nutrition via oesophagostomy tube feeding in dogs with severe acute pancreatitis Introduction Materials & Methods Animal selection Initial patient assessment and treatment Treatment groups Monitoring Statistical analyses Results Discussion Conclusion Chapter 8: Conclusion References Appendix Clinical Utility of SNAP cpl in Dogs with Acute Abdominal Disease

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11 11 Introduction Pancreatitis is an important disease of dogs. Acute pancreatitis can cause profuse vomiting with resultant dehydration and hypovolaemia (Simpson, 1993; Williams and Steiner, 2005). There is a high mortality rate associated with systemic effects of the disease, and dogs often require intensive treatment and hospitalisation (Ruaux and Atwell, 1998b). Predicting which animals will develop severe complications is difficult, although there is a significant association between fatality and existence of concurrent diseases such as diabetes mellitus, hyperadrenocorticism, and epilepsy (Cook et al., 1993; Hess et al., 1998; Ruaux and Atwell, 1998b). Traditional biochemical methods of diagnosing pancreatitis such as elevation of serum amylase and lipase concentrations are poor predictors of mortality (Mansfield et al., 2003). Despite an increase in the number of studies in the past decade addressing the diagnostic difficulties faced in canine pancreatitis, it is still unclear how sensitive and specific the currently used diagnostic modalities are. Part of this difficulty is a lack of a true gold standard, as pancreatic histopathology is seldom performed in severely unwell dogs with pancreatitis. It is also uncertain as to how the pancreatic inflammation seen histologically correlates to clinical severity, or indeed if it is the primary reason for presentation of the animal. Treatment of acute pancreatitis is non-specific and aimed at correcting secondary consequences of the disease (such as hypovolaemia or pain for example) rather than directly treating the pancreatic inflammation. There is a lack of controlled studies in treatment of this condition, and most recommendations are extrapolated from animal experimental models and human gastroenterology. An important aspect of developing any prospective treatment trials is to ensure that animals of equal clinical

12 12 severity are compared in studies, in order to ensure that any benefits are due to the treatment intervention rather than the study population.

13 13 Purpose This body of work aims to answer the following questions - In a cohort of dogs who display clinical signs that could be consistent with canine pancreatitis, what is the specificity and sensitivity of serum canine pancreatic-elastase 1, a potentially new diagnostic test? - In a sufficiently large cohort of dogs with diseases of similar severity to acute pancreatitis, what is the clinical specificity and sensitivity of canine pancreatic lipase? - Is there an effective and robust way to characterise the clinical severity of canine pancreatitis to aid in the development of future research into optimisation of treatment strategies? - Does the administration of plasma or minimal enteral nutrition have any potential benefits in the treatment of acute pancreatitis? - Does differing fat content of diet cause differing responses of the canine pancreas, and necessitate specific nutritional strategies? - Is early interventional enteral nutrition delivered proximal to the pylorus well tolerated by dogs with acute pancreatitis? - Is there evidence that early interventional enteral nutrition may be of benefit in treating dogs with severe acute pancreatitis?

14 14 List of abbreviations APACHE APN CCK CI CIRCI CRP ELISA EN ERCP FFP ICAM IL IV MEN MMP MODS NF-κB NG NJ NO NOS NPV PE-1 PLA PLI PMN PN PPN PPV PSTI RIA ROC ROS Acute Physiology and Chronic Health Evaluation Acute pancreatic necrosis Cholecystokinin Confidence Interval Critical illness related corticosteroid insufficiency C-reactive protein Enzyme-linked Immunosorbent Assay Enteral nutrition Endoscopic Retrograde Cholangiopancreatography Fresh frozen plasma Intercellular adhesion molecule Interleukin Intravenous Minimal (micro) enteral nutrition Matrix metalloproteinases Multiple organ dysfunction syndrome Nuclear factor kappa B Nasogastric (delivery of EN) Nasojejunal (delivery of EN) Nitric oxide Nitric oxide synthase Negative Predictive Value Pancreatic Elastase-1 Phospholipase Pancreatic lipase immunoreactivity Polymorphonuclear leukocytes Parenteral nutrition Partial parenteral nutrition Positive Predictive Value Pancreatic secretory trypsin inhibitor Radioimmunoassay Receiver operator characteristics Reactive oxygen species

15 15 RT-PCR SAA SIRS Spec-cPL TAP TLI TNF Real-time polymerase chain reaction Serum amlyoid A Systemic inflammatory response Specific canine pancreatic lipase Trypsinogen activation peptide Trypsin-like immunoreactivity Tumour necrosis factor