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Experimental Physiology 91.5 pp 935-941
DOI: 10.1113/expphysiol.2006.034421
© The Physiological Society 2006
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Vagal nerve activity contributes to improve the efficiency of pulmonary gas exchange in hypoxic humans

Shoji Ito1, Hiroshi Sasano1, Nobuko Sasano1, Junichiro Hayano2, Joseph A. Fisher3 and Hirotada Katsuya1

1 Department of Anaesthesiology and Medical Crisis Management2 Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan 3 Department of Anaesthesia, University Health Network, University of Toronto, Toronto, Canada, M5G 2C4


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
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 O2 (PaO2) and arterial oxygen saturation (SpO2) were measured, and alveolar-to-arterial PO2 difference (DA–aO2) was calculated. Anatomical dead space (VD,an), alveolar dead space (VD,alv) and the ratio of physiological dead space to tidal volume (VD,phys/VT) 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 PaO2 and SpO2 (P < 0.05 and P < 0.01, respectively) and an increase in DA–aO2 (P < 0.05). Anatomical dead space, VD,alv and VD,phys/VT 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 VD,an and VD,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.

(Received 10 May 2006; accepted after revision 26 June 2006; first published online 29 June 2006)
Corresponding author H. Sasano: Department of Anaesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho Mizuho-ku Nagoya, Aichi 467-8601, Japan.  Email: hirosasano{at}aol.com


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
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 (VD,phys/VT) and the fraction of intrapulmonary shunt. Giardino et al. (2003) also reported that the magnitude of RSA was associated with efficiency of pulmonary gas exchange in humans. In contrast, tonic activity of the pulmonary vagal nerves increases airway smooth muscle tone (Powell, 1998; Taylor et al. 1999) and will therefore reduce the anatomical dead space (VD,an). We hypothesized that both cardiac phasic and pulmonary tonic activity of the vagal nerve improve the efficiency of pulmonary gas exchange in humans. To test this hypothesis, we studied the effects of vagal nerve blockade with atropine on pulmonary mechanics and pulmonary gas exchange.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Subjects

Ten healthy, non-smoking volunteers (7 male and 3 female), aged 24–45 years, were studied. Their characteristics were (average (range)): age, 31.0 ± 8.3 (24–45) years; height, 167.6 ± 8.8 (150–178) cm; and mass, 63.5 ± 10.2 (47–80) kg. None had a history of cardiopulmonary disease or was taking any medication. The study was approved by the ethics committee of Nagoya City University Graduate School of Medical Sciences and adhered to the Principles of the Declaration of Helsinki. Informed written consent to participate in this study was obtained from each subject.

Measurements

The experiments were performed at a room temperature of 23–25°C at least 3 h after the subjects had ingested food. First, catheters (24 gauge; 19 mm long) were inserted into the antebrachial vein for drug injection and the radial artery for blood sampling. The subjects were seated upright and first breathed room air at uncontrolled tidal volume for about 10 min without a mouthpiece (precontrol) and then breathed air with reduced O2 concentration (12–13% O2; balance, N2) via a mouthpiece from a non-rebreathing circuit with a bellows acting as reservoir. A respiratory analyser (NICOTM, Novametrix Medical Systems Inc., 5 Technology Drive, Wallingford, Connecticut, USA) was installed in the respiratory circuit. Each subject was instructed to breathe in synchrony with a computer-generated signal (10 breaths min–1, 0.166 Hz, inspiratory-to-expiratory duration ratio = 1:1) and to keep the end-inspiratory and end-expiratory levels of the bellows constant. The gas flow was set equal to each subject's inspiratory minute volume Formula at an end-tidal partial pressure of CO2 (PET,CO2) of 25–35 mmHg (Fig. 1).


Figure 1
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  		Figure 1.  Diagram of breathing circuit used for both determining the minute ventilation Figure 1 atPET,CO2of 25–35 mmHg and maintaining VT constant during measurements
Each VT was composed of the gas flow during the inspiration and that to the spirometer during the previous expiration, because the gas flow was continuous and the ratio of inspiratory to expiratory duration was 1:1. Thus the difference in spirometer volume between end-inspiration and end-expiration represented half of the VT.

 
We monitored tidal concentrations of CO2 and tidal gas flow, as well as arterial oxygen saturation (SpO2). We automatically calculated the tidal volume (VT) for each breath with the respiratory analyser and transferred the values to a personal computer every 6 s. We calculated alveolar dead space (VD,alv) and VD,phys/VT by single-breath CO2 analysis from respiratory data and the arterial partial pressure of CO2 (PaCO2) obtained directly from arterial blood analysis (Fletcher et al. 1981) with the respiratory analyser (CHIRON 800 Series, Ciba Corning Diagnostics Corp., Medfield, Massachusetts, USA). The electrocardiogram (ECG; Nihon Koden Inc., Tokyo, Japan) was sampled and digitized at 1 kHz on a personal computer by an analog-to-digital converter (DI200, Dataq Instruments, Akron, OH, USA).

Once PET,CO2 had stabilized (less than 2 mmHg change over 2 min), arterial blood was withdrawn over 1 min and analysed immediately. Arterial oxygen saturation and breath-by-breath values for PET,CO2, VT and VD,an from 30 s before to 30 s following blood sampling (i.e. 2 min) were collected and averaged. Alveolar dead space and VD,phys/VT were calculated as described above (control values). Atropine (0.02 mg kg–1) was then administered intravenously. Six minutes after atropine administration, arterial blood was again withdrawn over 1 min, and the same respiratory parameters were obtained and recalculated as during the control phase (‘postatropine values’). Values of alveolar-to-arterial PO2 difference (DA–aO2) before and after atropine administration were calculated using equation:


Formula

where FIO2 is the fractional inspired O2, and respiratory quotient (R) is assumed to be 0.8.

The magnitude of RSA for the 2 min phases of normoxia (precontrol), control and postatropine with hypoxia, was assessed quantitatively by power spectrum analysis of the R–R interval (RRI) as the amplitude of RRI variability in the high-frequency (0.15–0.2 Hz) component (RRIHF; Hayano et al. 1994).

Statistical analysis

All data are expressed as the means ± S.D. The differences between control values and those postatropine or precontrol were compared with Student's paired t test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There was no difference in VT between postatropine and control values (978.3 ± 175.6 versus 984.6 ± 195.4 mmHg, P = 0.67). There was no difference in RRIHF between the precontrol (during normoxia) and control periods (before atropine administration during hypoxia; 50.8 ± 29.9 versus 48.5 ± 34.0 ms, P = 0.27). After atropine administration, RRIHF decreased (from 48.5 ± 34.0 to 6.7 ± 7.3 ms, P < 0.01; Fig. 2), and was accompanied by decreases in PaO2 (from 50.3 ± 5.2 to 48.3 ± 5.3 mmHg, P < 0.05) and SpO2 (from 89.3 ± 3.6 to 87.2 ± 3.9%, P < 0.01) and an increase in DA–aO2 (from 6.3 ± 5.4 to 8.4 ± 6.1 mmHg, P < 0.05; Fig. 3). End-tidal PCO2 and PaCO2, however, did not change (28.6 ± 4.0 versus 29.1 ± 3.6 mmHg, P = 0.24; and 30.1 ± 3.7 versus 29.6 ± 4.2 mmHg, P = 0.34, respectively). After atropine, there were increases in VD,an (from 185.4 ± 43.7 to 210.3 ± 50.1 ml, P < 0.01), VD,alv (from 93.4 ± 57.2 to 105.3 ± 66.7 ml, P < 0.05) and VD,phys/VT (from 0.29 ± 0.07 to 0.33 ± 0.07, P < 0.01) (Fig. 4).


Figure 2
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  		Figure 2.  The amplitude of R–R interval variability in high-frequency component (RRIHF) before (control) and after atropine administration (post)
RRIHF decreased after atropine administration. Data are expressed as means ± S.D., *P < 0.01 versus control values.

 

Figure 3
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  		Figure 3.  PaO2, DA – aO2andSpO2before (control) and after atropine administration (post)
PaO2 and SpO2 decreased and DA–aO2 increased after atropine administration. Data are expressed as means ± S.D.; *P < 0.01, #P < 0.05 versus control values.

 

Figure 4
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  		Figure 4.  VD,an, VD,alv and VD,phys/VT before (control) and after atropine administration (post)
After atropine, there were increases in VD,an, VD,alv and VD,phys/VT. Data are expressed as means ± S.D.; *P < 0.01, #P < 0.05 versus control values.

 
Figure 5 shows a representative trace obtained during the experiment and illustrates the protocol.


Figure 5
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  		Figure 5.  Representative traces obtained during the experiment, illustrating the protocol
Changes in autoregressive power spectra of R–R interval during 2 min of control and postatropine periods (top), R–R interval (RRI) during control period and postatropine administration (second from the top), change in breathing frequency (FB), VT, PET,CO2, SpO2 and VD,an during 2 min of control and postatropine periods (bottom set of panels) in a representative subject. The values obtained from analysis of arterial blood gas sampling, PaO2, VD,alv and VD,phys/VT are listed below the panels. In all panels, time 0 indicates when atropine was administered. RRIHF, the mean amplitude of high-frequency (0.15–0.20 Hz) component of R–R interval variation as the magnitude of respiratory sinus arrhythmia; PSD, power spectral density; RRI, R–R interval; FB, breathing frequency; VT, tidal volume; PET,CO2, end-tidal PCO2; SpO2, oxygen saturation from pulse oximetry; VD,an, anatomical dead space; PaO2, arterial PO2; VD,alv, alveolar dead space; VD,phys/VT, the ratio of physiological dead space to tidal volume.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is the first report, to our knowledge, to demonstrate that a decrease in RSA magnitude is associated with arterial deoxygenation and an increase in both physiological and alveolar dead space in humans. We demonstrated that vagal nerve blockade induced by atropine resulted in an increased anatomical and alveolar dead space and reduced PaO2 and SpO2 in subjects who inhaled hypoxic gas at constant respiratory frequency and tidal volume. These changes were accompanied by a decrease in RSA magnitude. These results are consistent with our hypothesis that both phasic cardiac vagal tone (resulting in increase of the magnitude of respiratory sinus arrhythmia) and tonic pulmonary vagal activity (increasing airway smooth muscle tone) contribute to the efficiency of pulmonary gas exchange in humans. An increase in phasic activity of the cardiac vagal nerve increases RSA magnitude. To the extent that heart rate may be related to pulmonary blood flow, this would increase the matching of perfusion to ventilation and decrease venous admixture and alveolar dead space (Hayano et al. 1996; Hayano & Yasuma, 2003). Tonic activity of the vagal nerve increases airway smooth muscle tone, resulting in tracheobronchial constriction (Dickstein et al. 1996), and therefore decreases anatomical dead space. Although pulmonary vagal nerve outflow changes throughout the respiratory cycle, its tonic activity has a key role in determining airway smooth muscle tone (Taylor et al. 1999).

Several features of our protocol require comment. Our subjects breathed gas with reduced O2 concentration in order to place the SpO2 in the steep part of the oxyhaemoglobin dissociation curve and increase our resolution of changes in venous admixture. Reduced O2 concentration in inhaled gas also constricts airway smooth muscles via vagal efferent nerves (Sorkness & Vidruk, 1986), thus increasing the change in anatomical dead space produced by atropine compared to what may have been seen if the subjects breathed room air. We were able to maintain constant frequency, VT and PET,CO2, thereby eliminating variation in these parameters as a source of variability in RSA (Hayano et al. 1994; Sasano et al. 2002) and dead space ventilation. Our protocol was carried out in spontaneously breathing subjects, rather than using positive pressure ventilation, which reverses the RSA pattern (Yli-Hankala et al. 1991), as a confounding factor.

Our results are consistent with previous reports (Hayano et al. 1996; Hayano & Yasuma, 2003; Giardino et al. 2003). Regarding cardiac phasic vagal activity, Hayano and co-workers demonstrated that artificially generated RSA improved pulmonary gas exchange in vagotomized dogs; VD,phys/VT and the fraction of intrapulmonary shunt decreased with the production of RSA (Hayano et al. 1996). Although they theorized that the change in RSA affected alveolar dead space, they only measured the physiological dead space without calculating alveolar dead space. We could demonstrate an increase in alveolar dead space accompanied by a decrease in RSA magnitude. Giardino et al. (2003) also reported that RSA magnitude was positively associated with pulmonary gas exchange efficiency, measured as the average ventilatory equivalent of CO2 and O2, in humans, and concluded that RSA might improve the efficiency of pulmonary gas exchange.

Regarding tonic pulmonary vagal activity, hypoxia and hypercapnia cause tracheobronchoconstriction, which is mediated by vagal efferent nerve activity (Nadel & Widdicombe, 1962; Dickstein et al. 1996). This may be a physiological adjustment to improve pulmonary gas exchange efficiency by reducing dead space. Nadel & Widdicombe (1962) reported that hypoxia and hypercapnia decreased tracheal volume and increased total lung resistance in dogs, and that the response was abolished with vagal nerve blockade by cooling. Dickstein et al. (1996) also showed that tracheal diameter decreased during hypercapnia and that the response was abolished by administration of atropine. They also implied that this might be a purposeful response to reduce dead space. These previous studies measured neither physiological dead space nor anatomical dead space. Also they failed to investigate the effect of atropine on pulmonary gas exchange.

The deterioration of pulmonary oxygenation after atropine administration in the present study appears to result from the mechanism of an increase in venous admixture associated with a decrease in RSA magnitude. Hayano et al. (1996) demonstrated in dogs that, in the presence of RSA, the fraction of intrapulmonary shunt was decreased by 51% compared with that in the absence of RSA. It is also possible that another mechanism, such as increased physiological dead space or cardiac output, or attenuation of hypoxic vasoconstriction, contributes to the deterioration of pulmonary oxygenation. The reduction in alveolar ventilation by the increase in physiological dead space (39 ml out of a tidal volume of 980 ml) results in a negligible calculated reduction in PaO2 (< 0.01 mmHg). Furthermore, DA–aO2 that should not be affected by PaCO2 also resulted in a deterioration of pulmonary oxygenation after atropine administration. Atropine may increase cardiac output as a result of increased heart rate, and the increase in cardiac output may reduce alveolar dead space. Although we did not measure cardiac output in the present study, an increase in heart rate resulting from atropine administration did not change cardiac output in conscious horses (Hinchcliff et al. 1991). Moreover, even if the cardiac output had increased in the present study, the increase in cardiac output would have decreased VD,phys/VT (Suwa et al. 1966), which is inconsistent with our results. Furthermore, it is unlikely that atropine attenuates hypoxic pulmonary vasoconstriction, leading to the decrease in PaO2, because hypoxic pulmonary vasoconstriction occurs mainly by local direct effects of hypoxia on alveolar epithelial cells and pulmonary vascular smooth muscles (Gurney, 2002), and because the vagal efferent nerve was reported to weaken (Chapleau et al. 1988) or did not influence it (Kazemi et al. 1972).

We performed this study in hypoxic conditions to enable the detection of changes in blood oxygen using a pulse oximeter. It is possible that hypoxia affected other respiratory factors, such as hypoxic pulmonary vasoconstriction, anatomical dead space and cardiac output. It may be worthwhile repeating this protocol in normoxic conditions.

In conclusion, the blockade of the vagal nerve with atropine resulted in an increase in anatomical and alveolar dead space 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 conscious humans.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Chapleau MW, Wilson LB, Gregory TJ & Levitzky MG (1988). Chemoreceptor stimulation interferes with regional hypoxic pulmonary vasoconstriction. Respir Physiol 71, 185–200.[CrossRef][Medline]

Coleridge HM, Coleridge JCG & Jordan D (1997). Integration of ventilatory and cardiovascular control systems. In The Lung: Scientific Foundations, pp. 1839–1849. Lippincott-Raven, Philadelphia.

Dickstein J, Greenberg A, Kruger J, Robicsek A, Silverman JA, Sommer LZ, Sommer DD, Volgyesi GA, Iscoe S & Fisher JA (1996). PCO2 affects tracheal tone during apnea in anesthetized dogs. J Appl Physiol 81, 1184–1189.[Abstract/Free Full Text]

Fletcher R, Jonson B, Cumming G & Brew J (1981). The concept of dead space with special reference to the single breath test for carbon dioxide. Br J Anaesth 53, 77–88.[Abstract/Free Full Text]

Giardino ND, Glenny RB, Borson S & Chan L (2003). Respiratory sinus arrhythmia is associated with efficiency of pulmonary gas exchange in healthy humans. Am J Physiol Heart Circ Physiol 284, H1585–H1591.[Abstract/Free Full Text]

Gurney AM (2002). Multiple sites of oxygen sensing and their contributions to hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol 132, 43–53.[CrossRef][Medline]

Hayano J, Mukai S, Sakakibara M, Okada A, Takata K & Fujinami T (1994). Effects of respiratory interval on vagal modulation of heart rate. Am J Physiol 267, 33–40.

Hayano J & Yasuma F (2003). Hypothesis: respiratory sinus arrhythmia is an intrinsic resting function of cardiopulmonary system. Cardiovasc Res 58, 1–9.[Abstract/Free Full Text]

Hayano J, Yasuma F, Okada A, Mukai S & Fujinami T (1996). Respiratory sinus arrhythmia-phenomenon improving pulmonary gas exchange and circulatory efficiency. Circulation 94, 842–847.[Abstract/Free Full Text]

Hinchcliff KW, McKeever KH & Muir WW 3rd (1991). Hemodynamic effects of atropine, dobutamine, nitroprusside, phenylephrine, and propranolol in conscious horses. J Vet Intern Med 5, 80–86.[Medline]

Kazemi H, Bruecke PE & Parsons EF (1972). Role of the autonomic nervous system in the hypoxic response of the pulmonary vascular bed. Respir Physiol 15, 245–254.[CrossRef][Medline]

Nadel JA & Widdicombe JG (1962). Effect of changes in blood gas tensions and carotid sinus pressure on tracheal volume and total lung resistance to airflow. J Physiol 163, 13–33.[Free Full Text]

Powell FL Jr (1998). Control of breathing. In Essential Medical Physiology, 2nd edn, ed. Johnson LR, pp. 289–303. Lippincott-Raven, Philadelphia.

Richter DW, Spyer KM, Gilbey MP, Lawson EE, Bainton CR & Wilhelm Z (1991). On the existence of a common cardiorespiratory network. In Cardiorespiratory and Motor Coordination, pp. 118–130. Springer-Velag, Berlin.

Sasano N, Vesely AE, Hayano J, Sasano H, Somogyi R, Preiss D, Miyasaka K, Katsuya H, Iscoe S & Fisher JA (2002). Direct effect of PaCO2 on respiratory sinus arrhythmia in conscious humans. Am J Physiol Heart Circ Physiol 282, 973–976.

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Yli-Hankala A, Porkkala T, Kaukinen S, Hakkinen V & Jantti V (1991). Respiratory sinus arrhythmia is reversed during positive pressure ventilation. Acta Physiol Scand 141, 399–407.[Medline]


   Acknowledgements
 
The work was supported by grants in aid for scientific research from the Ministry of Education, Science and Culture, Japan (no. 09771179).




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