The increased ventilatory response to exercise in pregnancy reflects alterations in the respiratory control systems ventilatory recruitment threshold for CO2

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Abstract

We tested the hypothesis that the magnitude of the pregnancy-induced increase in exercise hyperpnea is predictable based on the level at which PaCO2 is regulated at rest. We performed a detailed retrospective analysis of previous data from 25 healthy young women who performed exercise and rebreathing tests in the third trimester (TM3; 36.5 ± 0.2 weeks gestation; mean ± SEM) and again 20.4 ± 1.7 weeks post-partum (PP). At rest, arterialized venous blood was obtained for the estimation of PaCO2, [H+] and [HCO3]; and serum progesterone ([P4]) and 17β-estradiol ([E2]) concentrations. Duffin's modified hyperoxic rebreathing procedure was used to evaluate changes in central ventilatory chemoreflex control characteristics at rest. Breath-by-breath ventilatory and gas exchange variables were measured at rest and during symptom-limited incremental cycle exercise tests. At rest in TM3 compared with PP: PaCO2, [H+], [HCO3] and the central chemoreflex ventilatory recruitment threshold for PCO2 (VRTCO2) decreased, while ventilation (V˙E), [P4], [E2] and central chemoreflex sensitivity (V˙ES) increased (all p  0.001). The slope of the linear relation between V˙E and V˙CO2 during exercise was significantly higher in TM3 vs. PP (31.2 ± 0.6 vs. 27.5 ± 0.5, p < 0.001). The magnitude of this change in the V˙EV˙CO2 slope correlated significantly with concurrent reductions in each of the VRTCO2 (R2 = 0.619, p < 0.001), PaCO2 (R2 = 0.203, p = 0.024) and [HCO3] (R2 = 0.189, p = 0.030); and was independent (p > 0.05) of changes in [P4], [E2] and V˙ES. In conclusion, the increased ventilatory response to exercise in pregnancy can be explained, in large part, by reductions in the respiratory control system's resting PCO2 equilibrium point as manifest primarily by reductions in the VRTCO2.

Introduction

Human pregnancy is characterized by significant increases in minute ventilation (V˙E) with attendant reductions in arterial PCO2 (PaCO2 by 5–10 mmHg), plasma bicarbonate ([HCO3]) and arterial hydrogen ion concentrations ([H+]) both at rest and during standard submaximal exercise (Wolfe et al., 1998, Jensen et al., 2007). The physiological mechanisms of the increased ventilatory response to exercise in pregnancy, however, remain poorly understood, largely understudied and represent the primary focus of this study.

According to the “Oxford model” of ventilatory control (Lloyd and Cunningham, 1963, Cunningham et al., 1986), resting steady-state V˙E and PaCO2 are determined by chemoreflex and ‘other’ non-chemoreflex drives to breathe and their intersection with the metabolic hyperbola (Fig. 1), which represents the relationship between V˙E and PaCO2 at any given metabolic rate (V˙CO2), as defined by the alveolar gas equation for CO2: V˙E=(V˙CO2×863)/(PaCO2×[1VD/VT]), where Vd/Vt represents dead space ventilation. Because PaCO2 remains relatively unchanged from rest through moderate intensity exercise in healthy humans (Wasserman et al., 1973, Wasserman et al., 2005, Oren et al., 1981, Dempsey et al., 2006), including pregnant women (Pivarnik et al., 1992, Heenan and Wolfe, 2000, Heenan and Wolfe, 2003, Charlesworth et al., 2006, Weissgerber et al., 2006), it can be considered an ‘equilibrium point’ with respect to ventilatory control. Thus, the alveolar gas equation predicts that, in the setting of an unchanged Vd/Vt, the ventilatory response to any given increment in V˙CO2 during exercise will increase as the respiratory control systems resting PCO2 equilibrium point decreases. In other words, the ventilatory response to exercise would be greater when resting PaCO2 is regulated at 30 mmHg vs. 40 mmHg.

Indeed, Oren et al., 1981, Oren et al., 1991 previously showed that induction of a chronic partially compensated metabolic acidosis, which decreased resting PaCO2 by ∼7.5 mmHg, secondary to a parallel leftward shift (i.e., reduced threshold with no change in the slope or sensitivity) of the central ventilatory chemoreflex response curve to exogenous CO2 at rest, significantly increased V˙E by ∼10–30% at any given submaximal V˙CO2 during both incremental and constant-load cycle exercise in healthy men. Similarly, both Skatrud et al. (1978) and Robertson et al. (1982) found that administration of the synthetic progestin, medroxyprogesterone acetate, to healthy men significantly (i) decreased arterial, end-tidal and cerebrospinal fluid PCO2 by ∼5–6 mmHg at rest, despite no change in resting measures of central or peripheral chemoreflex sensitivity; and (ii) increased the ventilatory response to mild (V˙CO2=12L/min) and heavy (V˙CO2=23L/min) intensity cycle exercise by ∼15–20% and ∼25%, respectively.

We recently demonstrated that the hyperventilation and attendant hypocapnia/alkalosis of human pregnancy at rest results from a complex interaction between alterations in acid–base balance and other factors that directly affect V˙E, including increased non-chemoreflex and central chemoreflex drives to breathe (Jensen et al., 2008a). More specifically, we provided evidence to suggest that pregnancy-induced reductions in the respiratory control systems resting PCO2 equilibrium point could be largely accounted for by reductions in the central chemoreflex ventilatory recruitment threshold for CO2 (VRTCO2; refer to Fig. 4 in Jensen et al., 2008a), which in turn reflected the effects of long-term compensatory acid–base adjustments (i.e., reduced [HCO3]) on the relationship between the measured, PCO2, and actual, [H+], stimulus to the respiratory chemoreceptors.

The purpose of the current study, therefore, was to extend our previous work by testing the hypothesis that the magnitude of the increased ventilatory response to exercise in pregnancy can be explained, at least in part, by a reduction in the respiratory control systems resting PCO2 equilibrium point as manifest primarily by a decrease in the VRTCO2. To this end, we performed a comprehensive retrospective analysis of data from a group of 25 healthy women who underwent both exercise and rebreathing tests in the third trimester (TM3) and again ∼5 months post-partum (PP) as part of a recently published study from our laboratory designed to elucidate the physiological mechanism(s) of activity-related breathlessness in pregnancy (Jensen et al., 2009). To our knowledge, the present study is the first to examine the inter-relationships between the increased ventilatory response to (i) central chemoreflex stimulation by progressive hyperoxic–hypercapnia and (ii) symptom-limited incremental cycle exercise during pregnancy.

Section snippets

Subjects

Subjects included 25 healthy women, 20–40 years, parity ≤2 and experiencing uncomplicated singleton pregnancies. These women had no history of smoking or cardiovascular, respiratory, neuromuscular, musculoskeletal, metabolic and/or haematological disease; and were not taking medications (other than prenatal vitamins) that could affect the ventilatory and/or perceptual response to hyperoxic–hypercapnia. Subjects were recruited via posted announcements, newspaper advertisements and contact with

Results

Twenty-five healthy, young, non-smoking, regularly active women with normal baseline pulmonary function as determined by routine spirometry (FEV1 = 99 ± 2% predicted; FEV1/FVC = 101 ± 2% predicted) participated in experimental testing at 36.5 ± 0.2 weeks gestation and again 20.4 ± 1.7 weeks post-partum (Table 1). Sixteen women were nulliparous, seven were primiparous and two were para 2. Body mass, body mass index, serum [P4] and [E2] decreased, while resting PaCO2, [H+] and [HCO3] increased from TM3 to

Discussion

The main findings of this study support the following conclusions: (1) the hyperventilatory response to maternal exercise could not be easily explained by alterations in metabolic rate, dead space ventilation and/or central chemoreflex sensitivity; and (2) the increased ventilatory response to exercise in late pregnancy was associated with reductions in the respiratory chemoreflex control systems ventilatory recruitment threshold for CO2, which serves to decrease the regulated level of PaCO2 at

Acknowledgements

Financial support was provided by the Ontario Thoracic Society (Grant-in Aid); Ontario Thoracic Society Block Term Grant; and the William M. Spear Endowment Fund for Respiratory Research at Queen's University. D. Jensen was supported by a John Alexander Stewart Post-Doctoral Research Fellowship (Department of Medicine, Queen's University and Kingston General Hospital); a Queen's University Post-Doctoral Fellow Excellence in Research Award; and a Canadian Lung Association/Canadian Thoracic

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