The influence of age, sex, body size and lung size on the control and pattern of breathing during CO2 inhalation in Caucasians

doi:10.1016/0034-5687(72)90063-1

Respiration Physiology

Volume 16, Issue 3, December 1972, Pages 337-350

Respiration Physiolo...

https://doi.org/10.1016/0034-5687(72)90063-1 Get rights and content

Abstract

The pattern of breathing and the ventilatory response to CO₂ in the absence of hypoxia have been studied in 28 young adult men, 26 young adult women and 9 older men, all Caucasians, in an attempt to identify the causes of inter-individual variations. The responses have been represented by the parameters of the regression equations: Ve = S [P_CO₂-B] and Ve = M [Vt-K]. These have been compared between groups and subjected to a cross correlation analysis which also included age, height, weight, smoking habits, customary activity and the subdivisions of the total lung capacity. New findings are that S is significantly lower in women than in men, M is inversely related to the subject's age and K is proportional to body size. The other variables studied appear to be without influence on these parameters. The positive inter-correlation previously noted between S and M is confirmed, and K is also found to be highly correlation with S. It is suggested that the normal variations in vagal afferent activity in man may account for these inter-relations.

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The data regarding sex influences on the HcVR is also not homogeneous. Many studies have shown that the ventilatory response to CO2 is increased in healthy men compared with women during wakefulness (Berthon-Jones and Sullivan, 1984; Jensen et al., 2005; MacNutt et al., 2012; Patrick and Howard, 1972; White et al., 1983). On the other hand, Douglas et al. (1982) reported no difference in the HcVR between men and women, in wakefulness or sleep, when using either the absolute ventilatory response to CO2, corrected for body surface area, or the percentage change from the value determined in wakefulness.
Breathing is a vital behavior that ensures both the adequate supply of oxygen and the elimination of CO₂, and it is influenced by many factors. Despite that most of the studies in respiratory physiology rely heavily on male subjects, there is much evidence to suggest that sex is an important factor in the respiratory control system, including the susceptibility for some diseases. These different respiratory responses in males and females may be related to the actions of sex hormones, especially in adulthood. These hormones affect neuromodulatory systems that influence the central medullary rhythm/pontine pattern generator and integrator, sensory inputs to the integrator and motor output to the respiratory muscles. In this article, we will first review the sex dependence on the prevalence of some respiratory-related diseases. Then, we will discuss the role of sex and gonadal hormones in respiratory control under resting conditions and during respiratory challenges, such as hypoxia and hypercapnia, and whether hormonal fluctuations during the estrous/menstrual cycle affect breathing control. We will then discuss the role of the locus coeruleus, a sexually dimorphic CO₂/pH-chemosensitive nucleus, on breathing regulation in males and females. Next, we will highlight the studies that exist regarding sex differences in respiratory control during development. Finally, the few existing studies regarding the influence of sex on breathing control in non-mammalian vertebrates will be discussed.
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The hypoxic ventilatory response is typically used as a measure of peripheral chemoreflex sensitivity. Some studies have also reported that the hypoxic ventilatory response is increased in men compared to women (Morelli et al., 2004; Patrick and Howard, 1972; White et al., 1983) while others have reported that no sex difference exists (Jensen et al., 2005a; Tarbichi et al., 2003). One possible reason for these different findings is that menstrual cycle status was not controlled in some investigations, whereas other investigations made comparisons between men and women in either the follicular or luteal phase of the menstrual cycle.
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Comparisons among data from previous studies are made even more difficult by sex-related differences in anthropometric and lung function indexes. Although some previous studies, characterized by relatively small sample sizes, could not find significant differences in hypoxic sensitivity between the sexes,33‐35 our data, showing that the HVR is greater in men than in women, even after correction for body height, are in agreement with those of other previous works36‐39 and are consistent with the evidence suggesting that testosterone increases peripheral chemoreflex sensitivity to hypoxia.32,40 Similarly, our results point to the absence of sex differences in the HCVR in healthy subjects, as reported previously by other authors.35,41,42
Nocturnal periodic breathing occurs more frequently in men than in women with various clinical and pathophysiologic conditions. The mechanisms accounting for this sex-related difference are not completely understood. Acetazolamide effectively counteracts nocturnal periodic breathing, but it has been investigated almost exclusively in men. Our aim was to explore possible determinants of nocturnal periodic breathing in a high-altitude setting both in men and in women. We hypothesized that increased hypoxic chemosensitivity in men could be associated with the development of nocturnal periodic breathing at altitude more frequently than in women, and that acetazolamide, by leftward shifting the CO₂ ventilatory response, could improve nocturnal periodic breathing at altitude in a sex-independent manner.
Forty-four healthy lowlanders (21 women), randomized to acetazolamide or placebo, underwent cardiorespiratory sleep studies at sea level off treatment and under treatment on the first night after arrival at a 4,559-m altitude. Hypoxic and hypercapnic chemosensitivities were assessed at sea level.
Men, more frequently than women, exhibited increased hypoxic chemosensitivity and displayed nocturnal periodic breathing at altitude. Acetazolamide leftward shifted the CO₂ set point and, at altitude, improved oxygenation and reduced periodic breathing in both sexes, but to a larger extent in men. Hypoxic chemosensitivity directly correlated with the number of apneas/hypopneas at altitude in the placebo group but not in the acetazolamide group.
The greater severity of periodic breathing during sleep displayed by men at altitude could be attributed to their increased hypoxic chemosensitivity. Acetazolamide counteracted the occurrence of periodic breathing at altitude in both sexes, modifying the apneic threshold and improving oxygenation.
EU Clinical Trials Register, EudraCT; No.: 2010-019986-27; URL: https://www.clinicaltrialsregister.eu
Hypoxia-induced ventilatory responses in conscious mice: Gender differences in ventilatory roll-off and facilitation
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Citation Excerpt :
In humans, hypoxia-induced ventilatory responses (HVR) have been reported to be equal in females and males (Marcus et al., 1994) or greater in females (Aitken et al., 1986). In contrast, it has been reported that women have a lower HVR (White et al., 1983) and hypercapnic drive (Patrick and Howard, 1972; White et al., 1983) than men. Disparate findings have also been generated in animals.
The aim of this study was to compare the ventilatory responses of C57BL6 female and male mice during a 15 min exposure to a hypoxic–hypercapnic (H–H) or a hypoxic (10% O₂, 90% N₂) challenge and subsequent return to room air. The ventilatory responses to H–H were similar in males and females whereas there were pronounced gender differences in the ventilatory responses during and following hypoxic challenge. In males, the hypoxic response included initial increases in minute volume via increases in tidal volume and frequency of breathing. These responses declined substantially (roll-off) during hypoxic exposure. Upon return to room-air, relatively sustained increases in these ventilatory parameters (short-term potentiation) were observed. In females, the initial responses to hypoxia were similar to those in males whereas roll-off was greater and post-hypoxia facilitation was smaller than in males. The marked differences in ventilatory roll-off and post-hypoxia facilitation between female and male C57BL6 mice provide evidence that gender is of vital importance to ventilatory control.
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The extent to which aging affects respiratory control in postmenopausal women remains relatively unknown. In a cross-sectional study of 39 postmenopausal women (50–79 years), we examined the influence of age and fitness on the ventilatory responses to hypercapnia (HCVR; +8 mmHg) and exercise ( $Δ {\dot{V}}_{E} / Δ \dot{V} {CO}_{2}$ ) above and below the anaerobic threshold (AT). Data were analyzed using the full cohort, by age (younger postmenopausal: YPM, 50–64 years; and older postmenopausal: OPM, 65–79 years) and fitness as per our previous work (Active: $\dot{V} O_{2 max}$ ≥ 90% age-predicted values; and Sedentary: $\dot{V} O_{2 max}$ < 90% age-predicted values).
Although age did not affect the sensitivity of HCVR, Active women had significantly lower HCVR gain compared to sedentary women (Sedentary: 2.12 ± 0.80; Active: 1.57 ± 0.73, p = 0.02). In contrast, age, but not fitness, was inversely related to $Δ {\dot{V}}_{E} / Δ \dot{V} {CO}_{2}$ above AT (YPM: 46.8 ± 11.5; OPM: 34.8 ± 6.9, p < 0.01) which may be explained, at least in part, by age-related declines in lung function. HCVR and $Δ {\dot{V}}_{E} / Δ \dot{V} {CO}_{2}$ were not correlated.
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In this chapter, the impact of aging upon the respiratory system and how these changes may affect the regulation of blood gases are explored. While researching the chemical and mechanical sensors that initiate deviations from the inherent ventilatory rhythm it was found that the ventilatory response to hypoxic and hypercapnic challenges appears to be less sensitive in most, but not all, older individuals. It is possible that chemoreceptor sensitivity decreases with aging, but the available human evidence is more consistent with a reduced inspiratory muscle drive accompanying altered central nervous system function. However, animal studies have provided evidence of the carotid bodies becoming atrophied in older rats. Thus, it is possible that age-dependent reductions in ventilatory sensitivity can accompany changes to both chemoreceptor and medullary functions. In addition, the respiratory system obtains feedback from mechanical and metabolic sensors. Aging clearly affects mechanoreceptor feedback, with elderly individuals being less able to distinguish changes in elastic and resistive respiratory loads. Further, during exercise, particularly in habitually sedentary older people, there may be a significant expiratory flow limitation, with the tidal volume falling inside the closing capacity. In combination with changes in gas exchange, one finds that older individuals generally require greater minute ventilation when performing the same absolute work. Aging does not challenge the respiratory system to the point at which either the ventilatory or the gas exchange mechanisms may fail. Indeed, most changes occur very gradually and without significant adverse health implications, even for the most elderly of people.

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¹: Present address: Division of Human Biology and Behaviour, Faculty of Health Sciences, University of Ife, Ile-Ife, Nigeria.

²: Present address: Research Unit for Comparative Animal Respiration, University of Bristol, Bristol BS 8 1UG, England.

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The influence of age, sex, body size and lung size on the control and pattern of breathing during CO2 inhalation in Caucasians

Abstract

Lancet

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Lancet

Respir. Physiol.

J. Nutr.

Statistical Methods in Medical Research

Effect of mechanical loading on ventilatory response to CO2 and CO2 excretion

Brit. med. J.

Lung Function

The effect of inhalation of carbon dioxide on the respiration of the full-term and premature infant

J. Physiol. (London)

Respiration and oxygen supplies in the newborn

The respiratory response of man to hypoxia

Atmung und Säure-Basengleichgewicht in der Schwangerschaft

Pflügers Archiv

Weitere Untersuchungen über die Wirkung der Sexualhormone auf die Atmung

Pflügers Archiv

Control mechanisms determining rate and depth of respiratory movements

Respir. Physiol.

Cyclic fluctuations of the alveolar carbon dioxide tension during the normal menstrual cycle

Fertility and Sterility

The influence of age, sex, body size and lung size on the control and pattern of breathing during CO₂ inhalation in Caucasians

Effect of mechanical loading on ventilatory response to CO₂ and CO₂ excretion