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AN INVESTIGATION OF THE ANABOLIC ACTIONS OF BIOSYNTHETIC HUMAN GROWTH HORMONE AFTER INJURY BY BURNING A thesis sumitted for the degree of MASTER OF SURGERY in the UNIVERSITY OF LONDON H.J.C.R. Belcher, MB, BS(Lond), FRCS(Eng). The Blond-Mclndoe Centre, Queen Victoria Hospital, Holtye Rd, East Grinstead, SUSSEX. - 1 - ProQuest Number: U053257 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 com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest U053257 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 To my wife, Georgina - 2 - ABSTRACT Previous clinical trials in normal subjects and post-operative patients have shown that biosynthetic growth hormone preparations increase nitrogen retention. It has been suggested that their administration to injured patients may be beneficial. A clinical trial is presented of twelve adult burned patients of whom six were allocated to receive biosynthetic human growth hormone (somatropin) and six to form a control group. Injury by burning is followed by increases in resting energy expenditure and urinary nitrogen excretion, accompanied by insulin resistance and glucose intolerance. There is a generalised fall in plasma protein concentrations, including the somatomedin, insulin-like growth factor-I. Somatropin administration causes no change in the rate of protein oxidation, the positivity of nitrogen balance or, either serum somatomedin or plasma protein concentrations. It causes an increase in the insulin-resistance already present in burned patients. Two further studies are presented in which somatropin is compared with a placebo in both unburned and burned rats. Injury by burning causes weight-loss, an increase in urinary nitrogen excretion, a fall in the serum albumin and somatomedin concentrations, and a reduction in the strength of healing laparotomy wounds. Somatropin administration to unburned rats causes a small rise in the serum somatomedin concentration and a transient increase in wound-strength. It causes no increase in the positivity of nitrogen balance or weight-gain. Its administration to the burned rat causes no effect on the serum somatomedin concentration, nitrogen balance, weight-gain or wound-healing. These three studies show that somatropin has no anabolic effect soon after injury by burning. I postulate that this failure reflects the changes observed after injury in somatomedin concentrations and the responsiveness of somatomedins to somatropin. I conclude that somatropin and related compounds are not suitable for use as anabolic agents soon after injury by burning. - 3 - ACKNOWLEDGEMENTS The work for this thesis was carried out under the overall direction of M r. AJW. Sim and Professor HF. Dudley in the Department of Surgery at St. Mary’s Hospital to whom I am grateful for their advice on the direction and content of this thesis. This work was performed during my tenure of the Blond-Mclndoe Research Fellowship. The whole project, including my salary was funded by Lilly Research Ltd., who also provided the growth hormone preparations. I am particularly grateful to Dr. S. Wise from Lilly Research for his constant advice and encouragement during the project. The clinical work was conducted by myself in the Mclndoe Burns Centre at the Queen Victoria Hospital, East Grinstead. I am grateful for the support given to me by Professor J. Fabre, Director of the Blond-Mclndoe Centre, Dr. K. Judkins and Mr. NSB. Tanner, Consultants in charge of the Burns Centre, and to the nursing staff without whose help it would not have been possible; to Mrs. S. Shalaby, the Burns Centre dietician, who calculated the daily food intakes of the patients in the trial, and to Professor V. Marks in the Department of Chemical Pathology at the University of Sussex, for his advice on the assessment of glucose tolerance. The animal work was conducted by myself at the Department of Surgery at the Westminster Hospital. I am grateful to Professor H. Ellis for allowing me to do this work and for his constant help in its design, conduct and presentation. I would like to thank Mrs. C. Godfrey in the Animal House for her assistance during this time. I am grateful to Dr. M. Bayliss in the Department of Chemical Pathology at the Kent and Sussex Hospital, Tunbridge Wells for the majority of the blood and urine assays required during the clinical work; Dr. R. Beetham - 4 - ACKNOWLEDGEMENTS and Miss J. Sheldon in the Protein Reference Unit at the Westminster Hospital for the plasma protein assays; Dr. D. Teale in the Department of Biochemistry, St. Luke’s Hospital, Guildford for the insulin and IG F-I assays; Dr. R. Bhatt in the Department of Chemical Pathology at the Westminster Children’s Hospital for the nitrogen excretion assays for my animal work. I am also grateful to Professor T. Lewis and Dr. K. MacCrae for their advice on the use and presentation of statistics in this thesis. Finally, I thank my father for his help its preparation. - 5 - STATEMENT OF ORIGINALITY None of the work in this thesis has been performed before. All the experiments described were designed and carried out by myself. Since the development of biosynthetic human growth hormone (GH) preparations, a number of trials have been conducted which have investigated their anabolic activity in both normal subjects and post­ operative patients. A description of the first clinical trial using a biosynthetic GH preparation in burned patients is contained in chapter 8.. Similarly, previous animal studies have investigated the anabolic actions of GH and its effect on wound-healing. Descriptions of the first studies of the actions of a biosynthetic GH preparation in animals injured by burning are contained in chapters 9. and 10.. - 6 - CONTENTS Parts 7 Appendices 12 Figures 13 Tables 14 Additional material 16 Abbreviations and units 17 PART I - INTRODUCTION 19 Preamble 20 CHAPTER 1. HYPERMETABOLISM 1.1 Ebb and flow 21 1.2 The genesis of hypermetabolism 24 1.3 Mediation of hypermetabolism 28 1.4 Limitation of hypermetabolism 29 CHAPTER 2. MOBILISATION OF SUBSTRATE 2.1 Gluconeogenesis 32 2.2 Glucose metabolism 32 2.3 Fat breakdown 35 2.4 Protein breakdown 35 2.5 Amino-acid release 36 2.6 Nitrogen losses in burned patients 37 2.7 Protein depletion 38 CHAPTER 3. CONSEQUENCES OF MALNUTRITION 3.1 Injury and starvation 40 3.2 Consequences of malnutrition 40 3.3 The healing of incised wounds 41 3.4 Collagen and tensile strength 43 3.5 Nutrition and collagen deposition 44 3.6 Nutritional-depletion and wound-strength 44 3.7 Nutritional-repletion and wound-strength 45 3.8 Clinical implications 46 CHAPTER 4. FEEDING THE BURNED PATIENT 4.1 Improvements in the care of burned patients 48 4.2 Energy requirements 49 4.3 Energy and protein inter-relationships 50 - 7 - CONTENTS 4.4 Energy source 52 4.5 Route of administration 53 4.6 Formulation 54 4.7 Timing of feeding 55 4.8 Clinical implications 56 CHAPTER 5. ANABOLIC AGENTS 5.1 The need for anabolic agents 57 5.2 Anabolic steroids 57 5.3 Insulin 59 5.4 Naftidrofuryl (Praxilene) 60 5.5 Growth hormone 60 5.6 Recombinant growth hormone 62 5.7 Clinical implications 63 CHAPTER 6. GROWTH HORMONE PHYSIOLOGY 6.1 Structure 64 6.2 Secretion 64 6.3 Actions 67 6.4 Somatomedins 68 6.5 Somatomedin actions 69 6.6 Carbohydrate metabolism 70 6.7 Insulin and GH anabolism 72 6.8 Fat metabolism 72 6.9 Sodium and water metabolism 73 CHAPTER 7. GROWTH HORMONE AS. AN ANABOLIC AGENT 7.1 Animal pituitary-derived GH 75 7.2 Human pituitary-derived GH 76 7.3 Biosynthetic GH 77 7.4 Dosage 82 7.5 GH and clinical outcome 83 7.6 GH and wound-healing 84 7.7 Clinical potential of biosynthetic human GH 87 Summary 89 - 8 - CONTENTS PART II - CLINICAL STUDY 90 CHAPTER 8. AN INVESTIGATION OF BIOSYNTHETIC HUMAN GROWTH HORMONE (SOMATROPIN) IN BURNED PATIENTS Objectives 91 Material and methods 8.2.1 Introduction 92 8.2.2 Ethical approval and consent 93 8.2.3 Selection of patients 93 8.2.4 Randomization 95 8.2.5 Drug administration 95 8.2.6 Withdrawal criteria 96 8.2.7 Completion of study 96 8.2.8 Patients 98 8.2.9 Initial management 98 8.2.10 General management 99 8.2.11 Nutrition 100 8.2.12 Clinical data 100 8.2.13 Balance calculations 101 8.2.14 Calorimetry 102 8.2.15 Blood samples 104 8.2.16 Assay techniques 104 8.2.17 Glucose tolerance tests 105 8.2.18 Analysis and statistics 106 Results 8.3.1 Patients and severity of injury 108 8.3.2 Haematology 108 8.3.3 Calorimetry and energy expenditure 108 8.3.4 Dietary intake 113 8.3.5 Nitrogen metabolism 113 8.3.6 Plasma proteins 116 8.3.7 Fluid and electrolytes 119 8.3.8 Basal glucose and insulin concentrations 121 8.3.9 Glucose responses during IV G T T 121 8.3.10 Insulin responses during IVG TT 124 8.3.11 Side-effects of somatropin 128 Discussion 8.4.1 Introduction 129 8.4.2 Patients and general management 130 8.4.3 Haematological responses 131 8.4.4 Energy intake 132 8.4.5 Calorimetry 132 8.4.6 Energy expenditure 133 8.4.7 Somatropin and energy expenditure 134 8.4.8 Nitrogen metabolism 135 8.4.9 Potassium balance 136 8.4.10 Somatropin and nitrogen metabolism 137 8.4.11 Somatomedin responses 138 8.4.12 Plasma proteins 140 8.4.13 Sodium and fluid balance 142 8.4.14 Glucose metabolism 143 8.4.15 Somatropin and glucose metabolism 144 - 9 - CONTENTS 8.4.16 Trial withdrawals 146 8.4.17 Dosage 147 8.4.18 Conclusions 148 8.5 Principal findings 149 PART III - ANIMAL STUDIES .

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