FRESH FROZEN PLASMA THERAPY IN ACUTE PANCREATITIS BY TREVOR LEESE MA(Cantab), MB,BS(London), FRCS A Thesis Submitted for the Degree of Doctor of Medicine from The Department of Surgery, The University of Leicester June 1987 UMI Number: U010406 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Disscrrlation Publishing UMI U010406 Published by ProQuest LLC 2015. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 The material which this dissertation is based is my own independent work except where acknowledged. Trevor Leese May 1987 To Brigitte and the boys "That sweetbread gazing up at me Is not what it purports to be... Since it is neither sweet nor bread, I think I’ll take a bun instead." Ode to Sweetbread by Ogden Nash, 1953 CONTENTS Page Acknowledgements 6 Summary Chapter 1 Acute Pancreatitis Chapter 2 Protease Inhibitors with specific reference to their role in acute pancreatitis 78 Chapter 3 The scope of the present study 125 Chapter 4 An experimental model of acute pancreatitis 132 Chapter 5 A system for continuous intravenous infusion and body temperature monitoring in the unrestrained rat 160 Chapter 6 Buprenorphine analgesia in the rat model of acute pancreatitis 184 Chapter 7 Controlled trials of fresh frozen plasma therapy in experimental acute pancreatitis 198 Chapter 8 A multicentre prospective clinical trial of fresh frozen plasma therapy 221 in acute pancreatitis Chapter 9 Conclusions and prospects for research 245 Appendix 248 Bibliography 255 ACK N OWL edgilmekt: ' I would like to acknowledge with gratitude the following in the preparation of this thesis: Trent Regional Health Authority who funded the study through a Locally Organised Research Grant. Dr. DB Morton and Mr. P.Husken of the Department of Anatomy. University of Leicester^ for advice and help with the experimental model of acute pancreatitis. The late Mr. G.Fletcher and Mr. MA Squires of the Department of Medical Physics, Leicester Royal Infirmary, for assistance building the cages and infusion systems for the experimental study. The Department of Medical Illustration, Leicester Royal Infirmary, for the photographic plates. Dr. VE Mitchell, Mr. JA Revil, Mr. J O’Connor and Mrs. AR Mathers of the Department of Haematology, Leicester Royal Infirmary, for advice about the preparation of fresh frozen plasma and the blood counts and clotting studies in the experimental model. Dr. AF Winder and Dr.M.Holliday of the Department of Chemical - Pathology, Leicester Royal Infirmary, for the serum biochemistry in the animal model and the lactate dehydrogenase and antiprotease measurements in the clinical trial. Dr. KP West of the Department of Pathology, University of Leicester, for the preparation and interpretation of histological specimens. The Consultant Surgeons at the five hospitals involved in the clinical trial for allowing me to study patients under their care, and their juniors for their co-operation. Mrs. R.Aldwinckle for her patience during the typing of the drafts of this thesis and Mr. DP Fossard, Mr. DFL Watkin and Mr.AW Hall for their critical reading. Finally, 1 would like to offer my grateful thanks to Professor PRF Bell of the Department of Surgery, University of Leicester, for making the research facilities fully available to me during the course of this study and for his help and encouragement. SUMMARY Despite improvements in general supportative measures, the mortality from acute pancreatitis in the United Kingdom still approaches 10%. Although many specific therapies have been proposed, none has consistently been shown to improve outcome in controlled clinical trials. Intravenous fresh.frozen plasma has been advocated as a therapy for acute pancreatitis. It may supplement declining natural antiprotease capacity, particularly alpha^ macroglobulin which appears to have a central role in the elimination of disseminated pancreatic enzymes in man. Initially, the effect of fresh frozen plasma therapy on survival in an experimental model of acute pancreatitis was studied. A rat model of acute pancreatitis was established including the facility for continuous intravenous infusion of fluid. Intravenous therapy including fresh frozen plasma significantly improved survival at 12 hours in the model when compared with crystalloid (p<0.001) and colloid (p<0.01) controls. Subsequently a controlled clinical trial was performed involving five hospitals over a twenty three month period. Two hundred and two patients admitted with acute pancreatitis were randomised to receive either low volume fresh frozen plasma therapy (two units daily for three days) or colloid control. The major serum antiproteases were measured during the course of the disease. There were no significant differences between the two groups of patients in terms of clinical outcome. Serum alpha^ macroglobulin levels were reduced in both groups on day one and continued to fall significantly from day one to day three in the colloid control group (p<0.005) whilst remaining substantially unaltered in patients receiving fresh frozen plasma (p = 0.6527). The ability of relatively low volumes of fresh frozen plasma to supplement declining alpha, macroglobulin levels in the early stages of acute pancreatitis nas therapeutic implications. The administration of larger volumes of fresh frozen plasma or alpha^ macroglobulin concentrates may improve clinical outcome.