Dynamic ventilatory responses of females and males to acute isocapnic and poikilocapnic hypoxia

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Highlights

  • The biphasic response of ventilation during poikilocapnic and isocapnic hypoxia was studied in 14 female and 13 male subjects.

  • There were no effects of sex on parameters related to the size and timing of the growth and decay phases of ventilation.

  • However, the contributions of breathing frequency to the control of ventilation varied with sex and supplementation with CO2.

  • Control of CO2 during hypoxia significantly affected the growth and decay phases of ventilation in females and males.

Abstract

The human ventilatory response during acute hypoxia appears to be biphasic (growth and decay), but the effect of sex on the size and timing of this response is not known. We studied the effects of 15 min of poikilocapnic and isocapnic hypoxia (FiO2  0.10) on ventilation (V˙i) in 14 healthy female and 13 healthy male subjects. Parameters (amplitudes, time delays, time constants) describing individual V˙i responses were estimated using a biexponential function. There were no significant effects of sex on any of these parameters. CO2 regulation significantly altered the amplitudes of growth and decay phases and the onset of the latter phase in females and males. These human data suggest that sex does not affect the biphasic response of ventilation during hypoxia. However, additional evidence in this study suggests that sex influences the breathing frequency response during hypoxia and that this effect depends on the control of CO2.

Introduction

During acute hypoxia, ventilation rises to a peak response within a few minutes before falling to stable levels above those observed during normoxia (Easton and Anthonisen, 1988, Easton et al., 1986, Painter et al., 1993, Steinbeck and Poulin, 2007). This rise and fall in ventilation has been observed during poikilocapnic and isocapnic hypoxia, suggesting that the overall dynamic response consists of a growth and decay phase. The growth phase is linked to the decline in arterial PO2 and stimulation of the peripheral chemoreflex (Weil et al., 1970), but under poikilocapnic conditions it is also constrained by the fall in arterial PCO2 (Steinbeck and Poulin, 2007). Mechanisms underlying the decay phase are more obscure, perhaps related to decreased peripheral chemoreflex sensitivity to O2 (Painter et al., 1993) but not thought to involve CO2 (Easton and Anthonisen, 1988, Steinbeck and Poulin, 2007). The rise and fall in ventilation is linked predominantly to tidal volume, whereas the contribution of breathing frequency is less clear and might depend on the control of arterial PCO2 (Easton and Anthonisen, 1988, Easton et al., 1986, Steinbeck and Poulin, 2007).

A large number of human studies have explored the effect of sex on ventilatory responses during hypoxia, but the outcome of this research effort is very unclear. Most of these studies measured ventilation during isocapnic hypoxia and using a ‘progressive’ protocol (Weil et al., 1970) where the level of hypoxia was continuously increased to a severe level. The sensitivity of changes in ventilation under these conditions has been shown to be similar between females and males (Guenette et al., 2004, MacNutt et al., 2012, Marcus et al., 1994, Regensteiner et al., 1988), greater in females (Aitken et al., 1986) or greater in males (Kunitomo et al., 1988, McCauley et al., 1988, White et al., 1983). By contrast, only one study has assessed the biphasic response of ventilation in females and males during a constant level of hypoxia (isocapnic) sustained for 20 min and reported no effect of sex on ventilation (Sajkov et al., 1997). However, interpretation of this finding is difficult because of the significant, transient fall in end-tidal PCO2 in females (but not males) that might have blunted their initial ventilation responses. More recent evidence pertaining to the biphasic response from studies of C57BL6 mice exposed to poikilocapnic hypoxia indicated that, although the initial rise in ventilation was similar between sexes, the magnitude of decay in ventilation after the peak response was greater in females than males (Palmer et al., 2013).

Mathematical descriptions of the biphasic response of ventilation provide important information for modelling dynamic processes involved in respiratory control (Ben-Tal and Smith, 2010). Empirical models of ventilation responses during and after hypoxia have been developed (Clement and Robbins, 1993, Liang et al., 1997, Painter et al., 1993, Ward et al., 1992) for which physiological constructs such as peripheral and central chemoreflex sensitivities have been attributed to model parameters. Such models have also been designed to account for ventilatory suppression after hypoxia. There is, however, a need for a simpler empirical approach which can provide an accurate description of the biphasic response of ventilation during hypoxia and insight into size and timing of phases. This type of approach is used to study dynamic physiological responses during exercise (Lamarra, 1990, Reeder and Green, 2012) and hypoxia (Donnelly and Green, 2013), but to our knowledge has not been used to study ventilation during hypoxia.

The present study used empirical modelling to test the hypothesis that growth and decay phases are larger in females than males. Each phase was assumed to be exponential and defined by parameters representing its amplitude, time delay and time constant (Fig. 1). The hypothesis predicts that phase amplitudes (A1, A2), normalised appropriately, are higher in females. To explore involvement of arterial PCO2 in sex effects on breathing, we tested the hypothesis during poikilocapnic and isocapnic hypoxia and also examined responses of tidal volume and breathing frequency under these conditions.

Section snippets

Overview and design

To test the hypothesis we used a two-factorial, mixed design with sex and CO2 control (‘CO2′) as main factors. Each subject was screened and familiarised with hypoxia (FiO2 = 0.10) on a day prior to the experiment. During the experiment subjects rested in a quiet, darkened room in the lateral decubitus position for ∼150 min and were exposed to 15-min periods of poikilocapnic hypoxia (PH) and isocapnic hypoxia (IH). PH and IH were preceded by 15-min periods of normoxia, presented in a

Baseline

Significant effects of sex on baseline variables are shown in Table 1.

Temporal responses of cardiorespiratory variables during hypoxia

Breath-by-breath responses of end-tidal gases and respiratory variables, as well as beat-to-beat responses of SaO2%, during PH and IH were averaged over 1-min intervals for each subject and mean responses for females and males are presented in Fig. 2. Two female subjects exhausted the reservoir of hypoxic gas during PH in 13min and so all responses at later time points (t > 780 s) were excluded from both Fig. 2 and the 3-way

Main findings

In contrast to our hypothesis, sex did not influence the amplitudes or timing of growth and decay phases of the hypoxic ventilatory response and did not alter effects of regulating PetCO2 on these phases. There was, however, some evidence of sex influences on breathing frequency and its contribution to the hypoxic ventilatory response.

Sex-dependent effects on the hypoxic ventilatory response

Most human studies of sex and hypoxic ventilatory responses used ‘progressive’ protocols (Weil et al., 1970) during which inspired PO2 was decreased continuously

Conclusion

Evidence from this study suggests that sex does not affect the dynamic response characteristics of ventilation during poikilocapnic or isocapnic hypoxia. By contrast, the control and contribution of breathing frequency to these hypoxic responses varied between females and males, an effect of sex which appears to be related to arterial PCO2.

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