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Animal Models
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
The evolution of an animal model in inhalation toxicology is a slow process. Compared with the other routes of administration, this is due to the relatively smaller number of published inhalation studies available and the difficulties in implementing individually engineered solutions to address the specific features of the test agent or exposure patterns that attempt to mimic actual human exposure. Comparison of different species is sometimes difficult to perform, since the mode of exposure used for small rodents and for larger laboratory animals such as dogs, pigs, or non-human primates is different. Exposure conditions may differ in co-operative and non-co-operative animal subjects and may not be interchangeable from smaller to larger animal species due to variability in exposure paradigms. A range of exposure regimens has to be envisaged: exposure of groups of animals to an inhalation chamber equilibrium (t95) concentration (C) at a fixed exposure duration (t). Inhalation dose–response relationships can be established by variation of C or t. However, especially when simulating exposure patterns occurring during emergencies, t must be long enough relative to t95 to establish reliable concentration–response relationships. For volatile agents, C×t relationships may become increasingly non-proportional when C is high enough to cause respiratory depression, with decreased inhaled dose in one group and normal breathing in the next lower-exposure group. Especially for reactive and water-soluble gases examined in obligate nasal-breathing rodents, very high concentrations may gain access to the lower airways and alveoli, whereas lower concentrations are scrubbed in the airways of the upper respiratory tract. Hence, endpoints of toxicity to a fixed concentration but variable durations of exposure and vice versa may change as a result of differences in inhaled dose as well as the predominant site of dosing within the respiratory tract. In this context, it has to be recalled that each location of the tract has its own specific vulnerability and response to injury. Hence, critical etiopathologies and mechanisms of injury and recovery may change from one C×t to another.
Obstructive sleep apnea: personalizing CPAP alternative therapies to individual physiology
Published in Expert Review of Respiratory Medicine, 2022
Brandon Nokes, Jessica Cooper, Michelle Cao
The occluded nasopharynx has long been appreciated as a source of CPAP intolerance [37]. Nasal occlusion necessitates mouth breathing, leading to higher nasal CPAP pressures due to device-perceived leak, and thereby, greater patient discomfort [37]. Under normal circumstances, obligate nasal breathing is the rule during sleep and the evolution of nocturnal mouth breathing should prompt concern over compromised nasal patency [37]. Notably, increased nasal resistance is an independent risk factor for OSA development [38]. Additionally, mouth breathing has long been appreciated to make sleep-disordered breathing events more likely, potentially owing to decreases in the caliber of the retropalatal airspace [38,39]. Thus, OSA is more common in the presence of nasal allergies, a deviated nasal septum, prominent nasal valves, etc. [37].