Computer simulation clarifies mechanisms of carbon dioxide clearance during apnoea

BackgroundApnoeic oxygenation can come close to matching the oxygen demands of the apnoeic patient but does not facilitate carbon dioxide (CO2) elimination, potentially resulting in dangerous hypercapnia. Numerous studies have shown that high-flow nasal oxygen administration prevents hypoxaemia, and appears to reduce the rate of increase of arterial CO2 partial pressure (PaCO2), but evidence is lacking to explain these effects.MethodsWe extended a high-fidelity computational simulation of cardiopulmonary physiology to include modules allowing variable effects of: (a) cardiogenic oscillations affecting intrathoracic gas spaces, (b) gas mixing within the anatomical dead space, (c) insufflation into the trachea or above the glottis, and (d) pharyngeal pressure oscillation. We validated this model by reproducing the methods and results of five clinical studies on apnoeic oxygenation.ResultsSimulated outputs best matched clinical data for model selection of parameters reflecting: (a) significant effects of cardiogenic oscillations on alveoli, both in terms of strength of the effect (4.5 cm H2O) and percentage of alveoli affected (60%), (b) augmented gas mixing within the anatomical dead space, and (c) pharyngeal pressure oscillations between 0 and 2 cm H2O at 70 Hz.ConclusionsCardiogenic oscillations, dead space gas mixing, and micro-ventilation induced by pharyngeal pressure variations appear to be important mechanisms that combine to facilitate the clearance of CO2 during apnoea. Evolution of high-flow oxygen insufflation devices should take advantage of these insights, potentially improving apnoeic gas exchange

Strategies mitigating hypoxaemia in high-risk populations during anaesthesia and respiratory critical care: computational modelling studies

Assessing interventions applied during clinically-encounterable extreme scenarios is vital to enhance the quality of care. However, the studies that examine these situations are rare, ethically and clinically challenging. Computational modelling offers a reliable, efficient and almost ethical-free approach to investigate high-risk scenarios. This thesis evaluated interventions applied during (i) prolonged apnoea in obesity, (ii) airway obstruction in emergency crises, and (iii) hyperbaric oxygen therapy in severe hypoxaemic respiratory failure patients through a series of high-fidelity computational modelling studies. Worldwide, there are more than 650 million obese individuals and anticipated to increase. In the context of anaesthesia and critical care, obese subjects are at increased risks during general anaesthesia, such as airway difficulties and apnoea intolerance (rapid occurrence of hypoxaemia). Developing and quantifying methods to extend the safe (non-hypoxaemic) apnoea time would increase their safety remarkably during this procedure. The thesis showed that the use of high-flow nasal oxygen significantly delayed the safe apnoea time in a bank of obese virtual subjects. Persistent airway obstruction is not common in anaesthesia practice, but it could lead to catastrophic outcomes. Complete blockage of the upper airway was simulated until life-threatening hypoxaemia occurred, followed by relieving the obstruction and delivery of multiple patterns of tidal ventilation. Larger tidal volume did not achieve faster re-oxygenation compared to lower tidal volume. Globally, up to 20 million acute respiratory failure patients receive mechanical ventilation annually. The mortality of acute respiratory distress syndrome (ARDS) remains considerably high despite the implementation of the lung-protective ventilation strategy. A bank of severe ARDS virtual patients was configured and underwent maximum lung-protective ventilation strategy at atmospheric pressure (with high positive end-expiratory pressure [PEEP]) and hyperbaric pressure (with low PEEP). The hyperbaric oxygen significantly increased the oxygen delivery to tissues even with a low fraction of inspired oxygen. The thesis’s original contributions to knowledge are: first, it quantified the impact of airway obstruction and patency, high oxygen concentration and high-flow nasal oxygen, applied during apnoea, on the safe apnoea time in obesity. Second, it demonstrated that larger tidal ventilation during airway rescue is not necessary. Finally, it highlighted that hyperbaric oxygen therapy could provide adequate tissue oxygen delivery and may be considered as a rescue option for severe ARDS patients who remain hypoxaemic despite maximum lung-protective ventilation strategy

Strategies mitigating hypoxaemia in high-risk populations during anaesthesia and respiratory critical care: computational modelling studies

Assessing interventions applied during clinically-encounterable extreme scenarios is vital to enhance the quality of care. However, the studies that examine these situations are rare, ethically and clinically challenging. Computational modelling offers a reliable, efficient and almost ethical-free approach to investigate high-risk scenarios. This thesis evaluated interventions applied during (i) prolonged apnoea in obesity, (ii) airway obstruction in emergency crises, and (iii) hyperbaric oxygen therapy in severe hypoxaemic respiratory failure patients through a series of high-fidelity computational modelling studies. Worldwide, there are more than 650 million obese individuals and anticipated to increase. In the context of anaesthesia and critical care, obese subjects are at increased risks during general anaesthesia, such as airway difficulties and apnoea intolerance (rapid occurrence of hypoxaemia). Developing and quantifying methods to extend the safe (non-hypoxaemic) apnoea time would increase their safety remarkably during this procedure. The thesis showed that the use of high-flow nasal oxygen significantly delayed the safe apnoea time in a bank of obese virtual subjects. Persistent airway obstruction is not common in anaesthesia practice, but it could lead to catastrophic outcomes. Complete blockage of the upper airway was simulated until life-threatening hypoxaemia occurred, followed by relieving the obstruction and delivery of multiple patterns of tidal ventilation. Larger tidal volume did not achieve faster re-oxygenation compared to lower tidal volume. Globally, up to 20 million acute respiratory failure patients receive mechanical ventilation annually. The mortality of acute respiratory distress syndrome (ARDS) remains considerably high despite the implementation of the lung-protective ventilation strategy. A bank of severe ARDS virtual patients was configured and underwent maximum lung-protective ventilation strategy at atmospheric pressure (with high positive end-expiratory pressure [PEEP]) and hyperbaric pressure (with low PEEP). The hyperbaric oxygen significantly increased the oxygen delivery to tissues even with a low fraction of inspired oxygen. The thesis’s original contributions to knowledge are: first, it quantified the impact of airway obstruction and patency, high oxygen concentration and high-flow nasal oxygen, applied during apnoea, on the safe apnoea time in obesity. Second, it demonstrated that larger tidal ventilation during airway rescue is not necessary. Finally, it highlighted that hyperbaric oxygen therapy could provide adequate tissue oxygen delivery and may be considered as a rescue option for severe ARDS patients who remain hypoxaemic despite maximum lung-protective ventilation strategy

Effect of variable pre-oxygenation endpoints on safe apnoea time using high flow nasal oxygen for women in labour: a modelling investigation

BackgroundStudies of pulmonary denitrogenation (pre-oxygenation) in obstetric populations have shown high flow nasal oxygen therapy (HFNO) is inferior to facemask techniques. HFNO achieves median end-tidal oxygen fraction (FE′O2) of 0.87 after 3 min. As HFNO prolongs safe apnoea times through apnoeic oxygenation, we postulated that HFNO would still extend safe apnoeic times despite the lower FE′O2 after pre-oxygenation.MethodsThe Interdisciplinary Collaboration in Systems Medicine simulation suite, a highly integrated, high-fidelity model of the human respiratory and cardiovascular systems, was used to study the effect of varying FE′O2 (60%, 70%, 80%, and 90%) on the duration of safe apnoea times using HFNO and facemask techniques (with the airway open and obstructed). The study population consisted of validated models of pregnant women in active labour and not in labour with BMI of 24, 35, 40, 45, and 50 kg m−2.ResultsHFNO provided longer safe apnoeic times in all models, with all FE′O2 values. Labour and increased BMI reduced this effect, in particular a BMI of 50 kg m−2 reduced the improvement in apnoea time to 1.8–8.5 min (depending on the FE′O2), compared with an improvement of more than 60 min in the subject with BMI 24 kg m−2.ConclusionsDespite generating lower FE′O2, HFNO provides longer safe apnoea times in pregnant subjects in labour. Care should be taken when used in patients with BMI ≥50 kg m−2 as the extension of the safe apnoea time is limited

Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure

Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance “strength”) rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain—consequent to increased chemosensitivity and delay—the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = −0.68) oscillations (P < 0.001 for all, both groups combined). Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population

Studies of lung function

This thesis outlines the candidate's contribution to the study of Respiratory Physiology in two main areas 1. The effect of lung morphometry on lung function and 2. Reflex control of pattern of breathing.The work that makes up this thesis is laid out in largely chronological order describing the evolution of the investigations.The effect of bronchial tree structure on function was investigated using a number of new techniques developed by the author. These include a method of modelling the bronchial tree to previously unobtained detail in the form of a hollow cast. This enabled gas transit times to airways of 2-3 mm diameter to be measured and the contribution made by architecture, tissue compliance and the gradient of pleural pressure to the distribution of ventilation to be apportioned. This was the first time transit times to individual airways had been measured. Using these techniques the effect of bronchial tree structure on the phenomenon of separation of gas mixtures into their components during breathing, and the effect of the beating heart on the mixing of gases during breathing was quantified. The author's contributions to the investigation of neural control of breathing follow. A fortuitous observation that SO₂ blocks pulmonary stretch receptors (PSR) in rabbits, which took place while developing an animal model of bronchitis, lead to the observation of a non PSR mechanism determining inspiratory time (ti). Investigation of the action of rapidly adapting pulmonary receptors (RAR) using SO₂ confirmed their role in provoking sighs or augmented breaths and demonstrated that they terminated expiratory duration (tn) with a constant latency. A consistent effect of RARs on inspiration proved elusive until it was discovered that after provoking an augmented breath ft is refractory to the direct effects of RAR activity for about 2 minutes. This observation lead to the development of a theoretical model of control of ft via a central linking. This explained our observation of a non-PSR effect restricting ft after SO₂ block. Further investigations confirmed a role for RAR in control of breathing in conscious dogs. The action of RAR in initiating inspiration was demonstrated using PSR block. The same technique was used to elucidate the role played by PSR in shifts in functional residual capacity during changes in posture. An interesting observation made at this time is that although cough is primarily associated with RAR activity it can not be triggered from the lungs. The results of experiments demonstrating a similar role for RAR in conscious animals are presented.The influence of high frequency ventilation, on pulmonary receptors, the reflexes they produce and on the non-Newtonian properties of bronchial mucus is described.The way in which different species control their very different frequencies of breathing is included and the way pulmonary receptor activity is changed in some models of lung disease. The effects of modern anaesthetics on receptor activity and the effect of acupuncture as a respiratory stimulant are reported. The results of some investigations of human movement and tremor are presented. The candidates contributions to books and books published are described

Pulmonary function and cardiorespiratory fitness in idiopathic Parkinson's disease

PhD ThesisIdiopathic Parkinson’s disease (IPD) is a progressive neurodegenerative disorder, secondary to dopaminergic depletion, which primarily affects motor control via the basal ganglia. It is a multi system disease affecting dopaminergic neurones throughout the body. The Parkinsonian syndromes are associated with excess morbidity and mortality from respiratory causes. Pulmonary function studies have yielded conflicting results in IPD. There is a lack of high quality research examining the effect of exercise on pulmonary function and aerobic capacity in IPD. Understanding the pattern of any respiratory dysfunction and impairment in cardiorespiratory fitness in IPD, and interventions that could modify these, are of importance in dyspnoea, hypoxia, hypercapnia, pneumonia, speech, swallowing, sleep disordered breathing, daytime somnolence, acute respiratory failure, extubation difficulties, increased respiratory infections and reduced exercise tolerance and functional capacity. We recruited 103 individuals with IPD, at different disease stages, from the Northumbria Parkinson’s Disease Service to define the pattern of pulmonary dysfunction and respiratory muscle strength. 100 participants completed a cross-sectional study comprising demographics, questionnaires and comprehensive pulmonary function testing, including spirometry, flow volume loops, lung volume assessment and respiratory muscle strength testing. Of these 100, 32 volunteered for a randomised control trial (RCT) with additional measurements of aerobic capacity, assessed by cardiopulmonary exercise testing, and exercise capacity, assessed by six minute walk testing. The participants were randomised, 1:1, control:intervention. The intervention group participated in a 12 week, 3 times weekly, exercise intervention. The baseline assessments were repeated in both groups immediately after the intervention, with 27 completing the RCT. The cross-sectional pulmonary function study revealed an increased prevalence of obstructive spirometry, upper airway obstruction and inspiratory muscle weakness in this population. The randomised control trial demonstrated statistically significant improvements in the intervention group only in; aerobic capacity, exercise capacity, subjective parkinsonian symptoms, quality of life, depression, anxiety, sleep and sleepiness