THE USE OF LOCAL ANAESTHETIC AEROSOLS IN THE STUDY OF THE CONTROL OF BREATHING IN MAN AND DOG$ A Thesis submitted for the degree of Doctor of Philosophy in the Faculty of Science to the University of London by Russell Douglas Hamilton Department of Medicine Charing Cross and Westminster Medical School London March 1990 1 ABSTRACT In man, information from vagus nerve endings in the airways and lungs is thought to play a small role in the control of breathing at rest but has the potential to become important when ventilation increases and, more significantly, may cause the tachypnoea and breathlessness of some disease states. Unfortunately, few techniques exist which can be readily used to interrupt such information from the lungs in man. The main aim of this thesis was to investigate the role of these receptors in the control of breathing in man using inhaled local anaesthetic aerosols to block their discharge in a safe, reversible and selective manner. To achieve this, two aerosol systems were developed using 5% bupivacaine as the local anaesthetic. One aerosol (mass median diameter = 4.9pm) was shown by radioisotope scans to deposit predominantly in the larger airways while the other (mass median diameter = 1.0pm) deposited mainly in the lung periphery. In the studies performed in this thesis, the 1.0pm aerosol had no significant effects on breathing in dog or man, possibly because drug levels at the alveolar surface were too low. In contrast, in dogs the 4.9pm bupivacaine aerosol abolished reflexes believed to arise from receptors in the airways and, after a longer inhalation period, a reflex believed to be mediated by C-fibres in the lung periphery. In normal man, studies using the 4.9pm bupivacaine aerosol indicated that airway receptors act to minimize fluctuations in tidal volume at rest and are involved in limiting inspiration during exercise. The increased ventilatory response and breathlessness during C02 rebreathing after inhalation of this aerosol in normal and 1aryngectomized man demonstrates that the disruption of discharge from receptors in the airways and/or lungs can, under some circumstances, have a considerable effect on the control of breathing. Central intravenous injection of capsaicin produced a burning sensation in the chest (and cough) believed to be mediated by C-fibre endings in the lung; the burning could be abolished by the 4.9pm aerosol. Despite these encouraging results in normal subjects, inhalation of this aerosol had no effect on the tachypnoea or breathlessness of patients with interstitial lung disease during exercise. Further experiments with this useful technique are indicated to determine whether lung receptors produce the tachypnoea in active inflammatory lung disease. 2 For Ron and June Hamilton my parents 3 CONTENTS List of Tables 7 List of Illustrations 8 Abbreviations 10 Statement 11 Acknowledgements 12 SECTION I - INTRODUCTION AND BACKGROUND CHAPTER 1: INTRODUCTION 1.1 Overview 13 1.2 Afferent vagal information from the lung 14 1.3 Relative contribution of different 20 afferent vagal inputs 1.4 Rationale for the present studies 22 CHAPTER 2: AEROSOLS 2.1 THEORY AND BACKGROUND 2.1.1 Basic considerations 23 2.1.2 Mechanisms of deposition 23 2.1.3 Factors affecting deposition 24 2.1.4 Previous studies on aerosol deposition 27 2.1.5 Methods of aerosol deposition 29 2.1.6 Choice of generators 31 for the present studies 2.2 EXPERIMENTAL 2.2.1 Large particles 32 2.2.2 Small particles 42 CHAPTER 3: LOCAL ANAESTHETICS 3.1 Background 54 3.2 Structure 54 3.3 Mechanism of action 55 3.4 Differential sensitivities of nerve fibres 57 3.5 Structure-activity relationships 57 3.6 Metabolism 58 3.7 Systemic toxicity 58 4 3.8 Choice of local anaesthetic 59 for the present studies 3.9 Determination of bupivacaine concentration 63 in blood SECTION II - PHYSIOLOGICAL STUDIES DOGS - RESPIRATORY REFLEXES 4.1 Introduction 64 4.2 Methods 65 4.3 Results 68 4.4 Discussion 75 NORMAL MAN - RESTING STUDIES 5.1 Introduction 81 5.2 Methods 83 5.3 Results 87 5.4 Discussion 95 NORMAL MAN - SEARCH FOR PULMONARY CHEMOREFLEX 6.1 Introduction 99 6.2 Methods 104 6.3 Results 107 6.4 Discussion 114 NORMAL MAN - EXERCISE 7.1 Introduction 119 7.2 Methods 120 7.3 Results 123 7.4 Discussion 136 NORMAL AND LARYNGECTOMIZED MAN - C02 REBREATHING 8.1 Introduction 141 8.2 Methods 142 8.3 Results 145 8.4 Discussion 156 PATIENTS WITH INTERSTITIAL LUNG DISEASE - EXERCISE 9.1 Introduction 166 5 9.2 Methods 168 9.3 Results 171 9.4 Discussion 178 SECTION I I I - CONCLUSIONS CHAPTER 10 - CONCLUSIONS AND PLANS FOR FUTURE WORK 10.1 Conclusions 183 10.2 Proposals for future studies 187 APPENDICES 190 REFERENCES 191 6 LIST OF TABLES Table Description Page 2.1 Particle size distribution of large particle bupivacaine 34 aerosol (DeVilbiss 35B ultrasonic nebulizer). 2.2 Particle size distribution of small particle bupivacaine 47 aerosol (fluidized bed generator with Optimist). 2.3 Particle size distribution of small particle bupivacaine 50 aerosol (Unicorn nebulizer with Optimist). 2.4 Particle size distribution of small particle bupivacaine 51 aerosol (Turret nebulizer with Optimist). 3.1 Chemical and biological properties reported for four 56 typical local anaesthetics. 3.2 Duration of blockade of the cough reflex by three local 62 anaesthetic agents as large particle aerosols. 5.1 Scores from visual analogue scales used to assess central 90 nervous system effects of large particle aerosol inhalation. 5.2 Vigilance and reaction time before and after 91 large particle aerosol inhalation. 5.3 Effect of large particle aerosol inhalation on the 92 pattern of resting breathing in normal subjects. 6.1 Time of onset of the chest sensation after intravenous 113 injection of capsaicin and circulation time to the ear. 8.1 Details of 1aryngectomized subjects. 143 8.2 Cough reflex to mechanical probing in laryngectomized 149 subjects before and after large particle aerosol. 9.1 Details of patients with interstitial lung disease. 168 7 LIST OF ILLUSTRATIONS Figure Description Page 2.1 Example of the particle size distribution of an ideal 26 aerosol showing the log-normal nature of the distribution. 2.2 Fraction of aerosol particles deposited in the different 28 regions of the lung as a function of particle size. 2.3 Large particle aerosol generator: Devilbiss 35B ultrasonic 33 nebulizer with inspiratory and expiratory one-way valves. 2.4 Lung scan after inhalation of large and small particle Tc- 39 labelled bupivacaine aerosols together with perfusion scan. 2.5 Gamma counts in the right lung following inhalation of Tc- 40 labelled bupivacaine aerosols as a function of time. 2.6 Bupivacaine concentration and Tc activity in plasma 41 following inhalation of Tc-labelled bupivacaine aerosols. 2.7 Small particle aerosol generator: fluidized bed with 46 particle filter (Optimist). 2.8 Small particle aerosol generator: modified jet nebulizer 49 (Turret) and particle filter (Optimist). 4.1 Cardiovascular and respiratory effects of aerosol 69 inhalation and intravenous infusion of bupivacaine in dogs. 4.2 Pulmonary chemoreflex evoked by capsaicin injected into 71 the right ventricle in on dog. 4.3 Pulmonary chemoreflex to capsaicin before and after aerosol 72 inhalation and intravenous infusion of bupivacaine in dogs. 4.4 Hering-Breuer inflation reflex before and after aerosol 73 inhalation and intravenous infusion of bupivacaine in dogs. 4.5 Differential block of the pulmonary chemoreflex and the 74 inflation reflex during recovery from aerosol anaesthesia. 5.1 Copy of the visual analogue scales used to assess central 84 nervous system effects of saline and bupivacaine aerosol. 5.2 Concentration of bupivacaine in plasma during and after a 89 10 min inhalation of large particle bupivacaine aerosol. 5.3 Concentration of bupivacaine in plasma during and after a 94 20 min inhalation of small particle bupivacaine aerosol. 6.1 Effect of central and peripheral intravenous injection of 109 capsaicin in one normal human subject. 8 Figure Description Page 6.2 A&B: Effect of central injections of saline and capsaicin 110 on VT, TI? Te and fc for 5 breaths before and after injection. 7.1 Parts 1&2: Effect of large particle saline and bupivacaine 124 aerosols on the ventilatory response to exercise in normals. 7.2 Mean data over the last 5 min of exercise for normals after 126 large and small particle aerosols, and on repeat exercise. 7.3 Mean data for Tj and TE over the last 5 min of exercise in 127 normals after large particle saline and bupivacaine aerosol. 7.4 Effect of intravenous saline and bupivacaine infusion on 129 the ventilatory response to exercise in normal subjects. 7.5 Parts 1&2: Effect of performing two exercise tests 3 hours 131 apart without aerosols on the ventilatory response to exercise. 7.6 Parts 1&2: Effect of small particle saline and bupivacaine 134 aerosols on the ventilatory response to exercise in normals. 8.1 Effect of large particle saline and bupivacaine aerosol on 146 the ventilatory response to C02 in normal man. 8.2 Effect of large particle saline and bupivacaine aerosol on 147 breathlessness during C02 rebreathing in normal man. 8.3 Effect of large particle saline and bupivacaine aerosol on 150 the ventilatory response to C02 in laryngectomized man. 8.4 Effect of large particle saline and bupivacaine aerosol on 151 breathlessness during C02 rebreathing in laryngectomized man. 8.5 Effect of small particle saline and bupivacaine aerosol on 154 the ventilatory response to C02 in normal man. 8.6 Effect of small particle saline and bupivacaine aerosol on 155 breathlessness during C02 rebreathing in normal man.