1 Introduction Ventilatory control Two chapters in this thesis are dedicated to ventilatory control and the effect of drugs (morphine and oliceridine in Chapter 4) and type 2 diabetes (Chapter 5) on the ventilatory control system. In the field of anesthesiology, the study of ventilatory control has been of particular interest due to its implications for patient safety. Comprehending its underlying mechanisms is crucial, since disturbances in the normal respiratory rhythm generation may have severe cardiorespiratory consequences. The generation of respiratory rhythms occurs in specialized respiratory networks located in the pons and medulla. These networks receive afferent input from various sources, including the central and peripheral chemoreceptors, mechanoreceptors, and behavioral control from higher centers.29 The central chemoreceptors, dispersed in the hindbrain, sense minor changes in CO2/H+within the cerebrospinal fluid.30 The carotid bodies, the main peripheral chemoreceptors located in the fork of the carotid arteries, monitor hypoxia, hypercapnia as well as a variety of metabolic stimuli including arterial blood glucose concentrations.31 These chemoreceptors work together in an additive fashion. Upon metabolic acidosis, the input from the chemoreceptors activates the respiratory networks causing a hyperventilatory response, aimed a compensating the metabolic acidosis. A similar response is triggered by the exogenous administration of carbon dioxide, the hypercapnic ventilatory response or HCVR, and is used to determine the sensitivity of the ventilatory control system to CO2. The HCVR is particularly sensitive to the effects of opioids. In case of hypoxia, the carotid bodies are activated and a hyperventilatory response occurs that is biphasic.32 An initial acute response is followed by a slow decline, the hypoxic ventilatory decline. The secondary adaptation has a central origin, although its exact mechanism has yet to be elucidated. Apart from inducing a brisk hypoxia-induced hyperventilatory response, the carotid bodies induce an arousal response, as is observed in patients with obstructive sleep apnea. The obstruction and ensuring hypoxia stimulate the carotid bodies, causing an arousal response that clears the upper airways, followed by a short hyperventilatory response. InChapter 4, we obtain hypercapnic ventilatory responses induced by CO2 rebreathing according to the method developed by the Australian investigator D.J.C Read in the mid-1960s. Inhalation of 7% CO2 (in 93% O2) from a 46 liter rebreathing bag results in a linear increase in ventilation. We used the ventilation at an extrapolated end-tidal PCO2 of 55 mmHg as the main endpoint in our study. Recent studies from our laboratory indicate that this is the most sensitive parameter when determining the effect of drugs on ventilatory control.33 In Chapter 5, we use the more sophisticated dynamic end-tidal forcing 5
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