STUDIES ON THE BREAKING PATTERN IN MAN AT REST AND DURING SLEEP by Steven Andrew Shea A thesis submitted to the Faculty of Science, University of London for the degree of Doctor of Philosophy 1988 Department of Medicine, Charing Cross and Westminster Medical School, London. 2 ABSTRACT . This thesis quantifies the breathing pattern and the extent of the reproducibility of this pattern within an individual at rest and during sleep. From breath-by-breath measurements of respiratory frequency, tidal volune and end-tidal POO2 made under standardised conditions of relaxed wakefulness - with a minimum of sensory stimulation - the results show that differences between individuals are highly significantly greater than differences seen on repeated measurements within an individual: people tend to breathe in a reproducible and characteristic fashion. The basic respiratory pattern is shown to have long-term reproducibility for periods of up to 5 years and may be, to some extent, inherited since it is shown to be similar between identical twins. The individual’s ’respiratory personality’ also persists during deep non-rapid eye movement (non- REM) sleep when any forebrain influences upon breathing are minimal. Further studies, using similar techniques, examine the effect upon this basic respiratory pattern of some behavioural, metabolic and pulmonary reflex control mechanisms. These studies reveal that visual, and auditory stimulation, and altered cognitive activity (performing mental arithmetic) affects the pattern of breathing; principally by increasing respiratory frequency. However, these changes in breathing which occur between the different ’states’ are not solely behavioural responses since they are also related to increases in cerebral and/or somatic metabolism. This highlights the need to control environmental and behavioural variables when measuring resting breathing patterns. The pathologically excessive drive to breathe associated with interstitial lung disease which is present during wakefulness (thought to be mediated by pulmonary vagal afferent information) becomes reduced during deep non-REM sleep when cortical perception of afferent information is also reduced. This may indicate that the abnormally high drive to breathe during wakefulness is dependent upon cortical perception of afferent information from the diseased lungs. Recipients of heart-lung transplantation - who no longer possess thoracic vagal fibres - do not breathe any differently from normal either when awake at rest or during sleep. Hence, when the ventilatory demands are m i n i m a l the human ventilation system functions normally in the absence of a control loop involving pulmonary proprioceptors and the medullary respiratory centres. The thesis concludes that these data provide the basis for further experiments designed to elucidate the precise mechanisms underlying the determination of the basic resting breathing pattern. CONTENTS P«*e List of tables .......................................... 5 List of illustrations .......... ........................ 6 Abbreviations.............................. 8 Statement of involvement and previous publications....... 10 Acknowledgements ............ 11 PART I: BACKGROUND AND METHODS CHAPTER 1: GENERAL INTRODUCTION and AI M S ................. 12 CHAPTER 2: METHDDS (Common to most sections) ............ 23 Measurements ...................................... 23 A) Breathing................................. 23 i) "Noninvasive" estimates of breathing 23 a) Background................... 23 b) Method employed ............... 31 c) Appraisal of method .... 32 ii) Measurement of airflow, oxygen consumption, and carbon dioxide p r o d u c t i o n ........................ 35 B) Estimated blood gases .................... 36 i ) End-tidal POO2 ...... 36 ii) Transcutaneous POO2 ............... 37 iii) Arterial oxygen saturation....... 38 C) Other measurements ....................... 39 i) Cardiac frequency, systemic blood pressure, and qualitative index of a i r f l o w ......................... 39 ii) Neurophysiological signals ........ 39 Recordings ........................................ 40 Data analyses ............. 41 A) Computer analysis of respiratory inductance plethysmograph and other physiological signals B) Computer analysis of airflow signal ...... 45 C) Determination of relaxed wakefulness and sleep stages ............................. 47 General protocols and normal subjects ............. 47 A) "Noninvasive" Studies .................... 48 i) Studies during wakefulness ......... 48 ii) Studies during s l e e p .............. 49 B) "Invasive" Studies ....... 49 Statistical analyses .............................. 49 PART II: INDIVIDUALITY OF THE PATTERN OF BREATHING INTRODUCTION ............................................ 50 CHAPTER 3: BREATHING PATTERN DURING RELAXED WAKEFULNESS Introduction ...................................... 51 Methods (Additional to Chapter 2) ................. 52 Results ........................................... 55 D i s c u s s i o n........................................ 64 CHAPTER 4: INDIVIDUALITY OF BREATHING PATTERN ASSESSED OVER TIME Introduction ...................................... 74 Methods (Additional to Chapter 2) ................. 74 Results ............................................ 78 Discussion...... 86 CHAPTER 5: BREATHING PATTERNS OF IDENTICAL TWINS Introduction ...................................... 90 Methods (Additional to Chapter 2) ................. 90 4 UtKlHflS (continued) pafe Results ............................................ 93 D i s c u s s i o n .................. 103 CHAPTER 6: IS THE INDIVIDUALITY OF BREATHING PATTERN MAINTAINED DURING STAGE 4 SLEEP? Introduction ....................... 108 Methods (Additional to Chapter 2) ................. 110 Results....... 112 D i s c u s s i o n ............. ......................... 116 CONCLUDING DISCUSSION TO PART II ......................... 120 PART III: THE EFFECT OF AN ALTERED BHIAVIOURAL SITUATION UPON BREATHING INTRODUCTION ............................................ 125 CHAPTER 7: EFFECT OF VISUAL, AND AUDITORY STIMULATION AND OF MENTAL ARITHMETIC UPON BREATHING Introduction ................ 126 Methods (Additional to Chapter 2) ................. 126 Results ........................................... 132 D i s c u s s i o n ........................................ 141 CHAPTER 8: ARE THESE BEHAVIOURAL OR METABOLIC EFFECTS? Introduction........................... 145 Methods (Additional to Chapter 2) ................. 145 Results ......................................... 147 D i s c u s s i o n ...... 151 CONCLUDING REMARK TO PART III ............................ 153 PART IV: THE USE OF STATE 4 SLEEP TO ESTIMATE ANY PCREBRAIN CONTRIBUTION TO THE ABNORMAL PATTERN OF BREATHING IN PATIENTS CHAPTER 9: THE EXAMPLE OF INTERSTITIAL LUNG DISEASE Introduction............................ 154 Methods (Additional to Chapter 2) ................. 155 Results ........................................... 159 Discussion........................................ 163 PART V: THE INFLUENCE OF VAGAL AFFERENT INFORMATION UPON THE PATTERN OF BREATHING DURING RELAXED WAKEFULNESS AND STEEP CHAPTER 10: THE EXAMPLE OF CHRONIC LUNG DENERVATION PRODUCED BY COMBINED HEART-LUNG TRANSPLANTATION IN HUMANS Introduction..... ......................... 169 Methods (Additional to Chapter 2) ................. 170 Results ........................................... 175 Discussion ........................................ 184 PART VI: GENERAL CONCLUSIONS CHAPTER 11: GENERAL CONCLUSIONS .......................... 190 APPENDIX and REFERENCES: Appendix A: Computer Software ............................ 193 References: .............................................. 208 5 LIST OF TABUS Table Description .... page no. 1. Comparison between tided volumes derived from spirometry and from respiratory inductance plethysmography .................... 33 2. Comparison between respiratory variables derived, from respiratory inductance plethysmography, by computer analysis and by measurements from chart records; an example using an irregular breathing pattern.............................................. 44 3. Comparison between the physiological variables from four experimental runs, during relaxed wakefulness .................. 58 4. Results of selected statistical tests on respiratory data collected during relaxed wakefulness ........................... 60 5. Individuals* mean data for the primary respiratory variables for two studies separated by 4-5 years ............................. 83 6. Individuals* physical characteristics, pulmonary function and resting physiological variables, separated into pairs of identical twins .......................................................... 94 7. Individuals’ mean data for respiratory variables, measured with a pneumotachometer, separated into pairs of identical twins .... 97 8. Individuals* mean data for the primary respiratory variables, estimated with respiratory inductance plethysmography during relaxed wakefulness, separated into pairs of identical twins ........... 100 9. Comparison of breathing patterns between relaxed wakefulness and Stage 4 sleep, and between different periods of Stage 4 sleep ... 114 10. Experimental design for the study of the effects of auditory and of visual stimulation upon breathing ........................... 130 11. Auditory stimulation study: group means of all variables for four experimental runs during all experimental conditions...... 134 12. Visual stimulation study: group