Accurate measurements of arterial P CO 2 (P a,CO 2 ) currently require blood sampling because the end-tidal P CO 2 (P ET,CO 2 ) of the expired gas often does not accurately reflect the mean alveolar P CO 2 and P a,CO 2 . Differences between P ET,CO 2 and P a,CO 2 result from regional inhomogeneities in perfusion and gas exchange. We hypothesized that breathing via a sequential gas delivery circuit would reduce these inhomogeneities sufficiently to allow accurate prediction of P a,CO 2 from P ET,CO 2 . We tested this hypothesis in five healthy middle-aged men by comparing their P ET,CO 2 values with P a,CO 2 values at various combinations of P ET,CO 2 (between 35 and 50 mmHg), P O 2 (between 70 and 300 mmHg), and breathing frequencies (f ; between 6 and 24 breaths min −1 ). Once each individual was in a steady state, P a,CO 2 was collected in duplicate by consecutive blood samples to assess its repeatability. The difference between P ET,CO 2 and average P a,CO 2 was 0.5 ± 1.7 mmHg (P = 0.53; 95% CI −2.8, 3.8 mmHg) whereas the mean difference between the two measurements of P a,CO 2 was −0.1 ± 1.6 mmHg (95% CI −3.7, 2.6 mmHg). Repeated measures ANOVAs revealed no significant differences between P ET,CO 2 and P a,CO 2 over the ranges of P O 2 , f and target P ET,CO 2 . We conclude that when breathing via a sequential gas delivery circuit, P ET,CO 2 provides as accurate a measurement of P a,CO 2 as the actual analysis of arterial blood. Accurate measurement of arterial P CO 2 (P a,CO 2 ) is important for the clinical assessment of patients and, in physiological studies, for the assessment of control of breathing and cerebral blood flow. Currently, the reference standard for measuring P a,CO 2 is analysis of arterial blood via direct arterial puncture. This invasive approach has a number of disadvantages for both the subject (discomfort and potential arterial wall damage) and investigator (restricted mobility of the catheter insertion site, cost, time delay for blood analysis, and limited temporal resolution of changes in P a,CO 2 ). As a result, investigators have long sought a suitable non-invasive method to measure P a,CO 2 .Non-invasive methods of predicting P a,CO 2 from alveolar P CO 2 (P A,CO 2 ) consider the lung to be a tonometer in which CO 2 equilibrates between alveolar gas and capillary blood. In reality, however, the lung is not a single homogeneous time-invariant gas exchange compartment. Rather, P CO 2 varies in different regions of the lung as a result of differences in ventilation-to-perfusion matching (V A /Q ) throughout the lung and, in each lung region, throughout the respiratory cycle (Dubois et al. 1952;Lenfant, 1967). The contribution to the P a,CO 2 of blood passing each alveolus reflects the average P CO 2 in that alveolus during the respiratory cycle (Jones et al. 1979;Robbins et al. 1990). P a,CO 2 , then, reflects the timeand flow-weighted averages of all alveolar ventilatory fluctuations in allV A /Q regions throughout the lung, i.e. the mean P A,CO 2 (Lenfant, 1967). As a result, the r...

In-depth investigation of cerebrovascular blood flow and MR mechanisms underlying the blood oxygenation level dependent signal requires precise manipulation of the arterial partial pressure of carbon dioxide and oxygen, measured by their noninvasive surrogates, the end-tidal values. The traditional methodology consists of administering a fixed fractional concentration of inspired CO 2 , but this causes a variable ventilatory response across subjects, resulting in different values of end-tidal partial pressures of CO 2 and O 2 . In this study, we investigated whether fine control of these end-tidal partial pressures would improve stability and predictability of blood oxygenation level dependent and arterial spin labeling signals for studying cerebrovascular reactivity. In 11 healthy volunteers, we compared the MR signals generated by the traditional fixed fractional concentration of inspired CO 2 method to those of an automated feed-forward system, a simpler, safer, and more compact alternative to dynamic end-tidal forcing systems, designed to target constant end-tidal partial pressures of CO 2 and O 2 . We found that near square-wave changes in end-tidal partial pressure of CO 2 of 5, 7.5, and 10 mm Hg (61.01 mm Hg within two to three breaths) and constrained changes in the end-tidal partial pressure of O 2 (<10 mm Hg) induced cerebral vascular reactivity measurements with faster transitions, together with improved stability and gradation, than those achieved with the traditional fixed fractional concentration of inspired CO 2 method. Magn Reson Med 64:749-756,

The study of the biology of evolution has been confined to laboratories and model organisms. However, controlled laboratory conditions are unlikely to model variations in environments that influence selection in wild populations. Thus, the study of “fitness” for survival and the genetics that influence this are best carried out in the field and in matching environments.Therefore, we studied highland populations in their native environments, to learn how they cope with ambient hypoxia. The Andeans, African highlanders and Himalayans have adapted differently to their hostile environment.Chronic mountain sickness (CMS), a loss of adaptation to altitude, is common in the Andes, occasionally found in the Himalayas; and absent from the East African altitude plateau.We compared molecular signatures (distinct patterns of gene expression) of hypoxia-related genes, in white blood cells (WBC) from Andeans with (n = 10), without CMS (n = 10) and sea-level controls from Lima (n = 20) with those obtained from CMS (n = 8) and controls (n = 5) Ladakhi subjects from the Tibetan altitude plateau. We further analyzed the expression of a subset of these genes in Ethiopian highlanders (n = 8). In all subjects, we performed the studies at their native altitude and after they were rendered normoxic.We identified a gene that predicted CMS in Andeans and Himalayans (PDP2). After achieving normoxia, WBC gene expression still distinguished Andean and Himalayan CMS subjects.Remarkably, analysis of the small subset of genes (n = 8) studied in all 3 highland populations showed normoxia induced gene expression changes in Andeans, but not in Ethiopians nor Himalayan controls. This is consistent with physiologic studies in which Ethiopians and Himalayans show a lack of responsiveness to hypoxia of the cerebral circulation and of the hypoxic ventilatory drive, and with the absence of CMS on the East African altitude plateau.

The aim of this study was to test our hypothesis that both phasic cardiac vagal activity and tonic pulmonary vagal activity, estimated as respiratory sinus arrhythmia (RSA) and anatomical dead space volume, respectively, contribute to improve the efficiency of pulmonary gas exchange in humans. We examined the effect of blocking vagal nerve activity with atropine on pulmonary gas exchange. Ten healthy volunteers inhaled hypoxic gas with constant tidal volume and respiratory frequency through a respiratory circuit with a respiratory analyser. Arterial partial pressure of O 2 (P aO 2 ) and arterial oxygen saturation (S pO 2 ) were measured, and alveolar-toarterial P O 2 difference (D A−aO 2 ) was calculated. Anatomical dead space (V D,an ), alveolar dead space (V D,alv ) and the ratio of physiological dead space to tidal volume (V D,phys /V T ) were measured. Electrocardiogram was recorded, and the amplitude of R-R interval variability in the high-frequency component (RRIHF) was utilized as an index of RSA magnitude. These parameters of pulmonary function were measured before and after administration of atropine (0.02 mg kg −1 ). Decreased RRIHF (P < 0.01) was accompanied by decreases in P aO 2 and S pO 2 (P < 0.05 and P < 0.01, respectively) and an increase in D A−aO 2 (P < 0.05). Anatomical dead space, V D,alv and V D,phys /V T increased (P < 0.01, P < 0.05 and P < 0.01, respectively) after atropine administration. The blockade of the vagal nerve with atropine resulted in an increase in V D,an and V D,alv and a deterioration of pulmonary oxygenation, accompanied by attenuation of RSA. Our findings suggest that both phasic cardiac and tonic pulmonary vagal nerve activity contribute to improve the efficiency of pulmonary gas exchange in hypoxic conscious humans. The cardiovascular system mediates the interchange of oxygen and carbon dioxide between the lungs and the tissues (Richter et al. 1991;Coleridge et al. 1997). A high degree of co-ordination between the cardiovascular and respiratory system has been required from the earliest stages of vertebrate evolution (Taylor et al. 1999). The vagal nervous system is involved in the function of both systems and may play a role in co-ordinating their activity. Phasic activity of the cardiac vagal outflow is closely linked to respiration and produces respiratory sinus arrhythmia (RSA), which causes increases in heart rate during inspiration and decreases during expiration. It may improve pulmonary gas exchange by matching pulmonary capillary perfusion to alveolar ventilation during each respiratory cycle (Hayano et al. 1996;Hayano & Yasuma, 2003). Hayano et al. (1996) demonstrated that in vagotomized dogs whose heart rates were controlled with a pacemaker, artificially generated RSA improved the efficiency of gas exchange as a result of decreasing the ratio of physiological dead space to tidal volume (V D,phys /V T ) and the fraction of intrapulmonary shunt. Giardino et al. (2003) also reported that the magnitude of RSA was associated with efficiency of pulmonary gas exch...