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Upper airway resistance during progressive hypercapnia and progressive hypoxia in normal awake subjects
Respiration Physiology 124 (2000) 35 – 42 www.elsevier.com/locate/resphysiol
Upper airway resistance during progressive hypercapnia and progressive hypoxia in normal awake subjects Eric Verin a,*, Catherine Tardif a, Jean Paul Marie b, Xavier Buffet b, Yann Lacoume a, Pascal Delapille a, Pierre Pasquis a a
Ser6ice de Physiologie Respiratoire et Sporti6e, CHU de Rouen, Hopital de Bois Guillaume-147 A6enue du Mare´chal Juin, 76230 Bois Guillaume, France b Ser6ice d’ORL et chirurgie cer6ico faciale, CHU de Rouen, Hopital Charles Nicolle-1 rue de Germont 76031, Rouen Cedex, France Accepted 28 August 2000
Abstract Ventilatory motor output is known to influence the upper airway. Although inspiratory upper airway resistance decreases during progressive hypoxia or hypercapnia, the effects of hypoxia and hypercapnia on expiratory upper airway resistance remain unknown. In the present study, we attempted to examine whether the expiratory and the inspiratory upper airway resistances were modified in the same way by progressive hyperoxic hypercapnia or by progressive normocapnic hypoxia. Nine healthy subjects (five males, four females, 33 9 9 years) participated in the study. Inspiratory upper airway (iUAR) and expiratory upper airway resistances (eUAR) were calculated at flow 300 ml s − 1. Both resistances were obtained during a baseline period and during progressive hyperoxic hypercapnia or progressive normocapnic hypoxia. In all subjects, iUAR and eUAR decreased significantly during hypercapnic or hypoxic challenge (PB0.05). eUAR was always lower than iUAR during hypercapnic challenge (PB 0.0001) and during hypoxic challenge (P B0.0001). The authors conclude that expiratory upper airway resistance, as with inspiratory resistance, decreases during progressive hypercapnia or during progressive hypoxia. Pharyngeal dilator or constrictor muscle activities may be implicated. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Control of breathing; Respiratory drive; Hypercapnia; Progressive; Airway resistance; Hypoxia; Mammals; Humans; Upper airways; Resistance
1. Introduction
* Corresponding author. Tel.: +33-232-889222; fax: + 33232-889139. E-mail address: [email protected] (E. Verin).
In both animals and humans, the upper airway plays a role in determining the breathing pattern during inspiration and expiration. In humans, during inspiration, activation of diaphragm and upper airway dilator muscles is closely synchro-
0034-5687/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 0 3 4 - 5 6 8 7 ( 0 0 ) 0 0 1 8 9 - 4
36
E. Verin et al. / Respiration Physiology 124 (2000) 35–42
nised, and like the diaphragm, upper airway dilator muscle activities increase during hypercapnic and hypoxic stimulations (O8 nal et al., 1981a,b). This upper airway dilator muscle activation permits the upper airway to resist collapsing during diaphragmatic contraction. In sleep apnea syndrome, airway abnormalities occur both during expiratory and inspiratory phases of ventilation. Inspiratory anomalies (apnea or hypopnea) were first discovered and explored by Remmers et al. (1978). However, more recent studies have demonstrated that narrowing of the upper airway can also occur during expiration. Increased expiratory resistance (Sanders et al., 1985) and prolonged expiratory air flow (Stanescu et al., 1996) are associated with the breath preceding the initial occluded inspiratory effort in occlusive apnea. Lofaso et al. (1998) have demonstrated that an increase in expiratory resistance is of a similar magnitude as the increase in inspiratory resistance. It also promotes dynamic hyperinflation, increases inspiratory work and could participate in CO2 retention or O2 deprivation during sleep. Therefore, a decrease in upper airway resistance during hypercapnia and hypoxia should facilitate ventilation. In healthy awake subjects, inspiratory upper airway resistance has previously been demonstrated to decrease during progressive hyperoxic hypercapnic challenge and progressive normocapnic hypoxic challenge (Se´rie`s et al., 1989; Dinh et al., 1991; Maltais et al., 1991). In the present study, we attempted to examine if expiratory upper resistance was also modified by progressive hyperoxic hypercapnia or by progressive normocapnic hypoxia, in healthy awake subjects.
2. Method
2.1. Subjects Nine healthy subjects (five males, four females) participated in the study. Seven subjects underwent hypercapnic challenge, six subjects underwent hypoxic challenge (four subjects underwent the two challenges). Their mean age was 3399 years with a normal body mass index (229 2 kg
m − 2) (Table 1). No subjects were on medication or complained of symptoms, which suggest of sleep apnoea syndrome. Each subject volunteered to participate in the study and gave their informed consent prior to participating in the study.
2.2. Measurements We independently measured upper airway resistance and respiratory response to chemical stimulations, with two different systems.
2.2.1. Upper airway resistance
2.2.1.1. Nasal flow. A tightly fitting translucent mask (continuous positive airway pressure mask, Respironics, Murrisville, PA) was placed over the nose, connected to a Fleish n°.3 pneumotachograph (Hans Rudolph, Kansas City, MO) to measure instantaneous flow. 2.2.1.2. Hypopharyngeal pressure. Hypopharyngeal pressure, or supralaryngeal pressure, was measured with a catheter (XRO feeding tube, 50 cm length, external diameter=2.4 mm; internal diameter=1.4 mm, Vygon®, Ecouen, France) connected to a Valydine MP 45-1 differential pressure transducer (9100 cmH2O, Valydine, Northridge, CA). It was passed through the mask and introduced into one nostril, after topical anaesthesia (lidocaine spray 5%) and lubrication of the catheter (lidocaine gel 2%). The tip was inserted into the lower part of the hypopharynx, as far down as the patient could tolerate without gag or discomfort in swallowing (189 2 cm from the nostrils). In this position, it was posterior to the epiglottis (Hudgel, 1986). The side of the catheter was perforated with two holes near its sealed tip. To assure upper airway catheter patency and keep the catheter free of secretion, equal bias flow of 0.1·l·min of compressed air was passed through each catheter. Pressure measurement was referenced to the mask. Pressure and flow were recorded on an electrostatic system Gould ES 2000® (Gould Instrument System, Valley View, OH).
47 25 24 44 22 28 31 42 31 33 9
Age years
F M M F F F M M M
Sex
22 20 25 21 21 25 25 20 19 22 2
BMI kg m−2
– 1.25 – 1.05 0.87 0.72 1.08 1.13 1.88 1.14 0.37
VE/PETCO2 l min−1 mmHg−1 – 0.03 – 0.02 0.06 0.02 0.04 0.04 0.09 0.04 0.03
VT/TI/PETCO2 l s−1 mmHg−1
n.a. – 0.34 0.68 0.36 0.66 0.25 0.24 0.42 0.20
P0.1/PETCO2 cmH2O·mmHg−1
−1.20 −0.88 −0.62 –0.71 – – −1.70 −0.58 – −0.95 0.43
VE/SaO2 min−1 %−1
n.a.: data non available. Seven subjects underwent an hypercapnic challenge and six subjects an hypoxic challenge (four subjects underwent the two challenges).
a
AB AJ AT CT DC SB VE XB YL Mean S.D.
Subjects
Table 1 Anthropometric data and indices of ventilatory drive of the nine subjectsa
−0.06 −0.08 −0.03 −0.04 – – −0.06 −0.05 – −0.05 0.02
VT/TI/SaO2 l sec−1 %−1
−0.44 −0.70 −0.25 −0.35 – – −0.60 −0.14 – −0.41 0.21
P0.l/SaO2 cmH2O %−1
E. Verin et al. / Respiration Physiology 124 (2000) 35–42 37
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E. Verin et al. / Respiration Physiology 124 (2000) 35–42
2.2.1.3. Upper airway resistance. Because there is a non-linear relationship between airflow and pressure, inspiratory and expiratory resistances were calculated at flow 300 ml·sec. Inspiratory and expiratory upper airway resistances were calculated by the ratio of the pressure to the flow (respectively iUAR and eUAR). 2.2.2. Hypercapnic challenges and hypoxic challenges A 5 l bag, connected to inspiratory and expiratory lines completed the rebreathing circuit. A Hans Rudolph effort valve was connected to a pneumotachograph n°3 (Hans Rudolph, Kansas City, MO), to separate the inspiratory and the expiratory lines. End tidal CO2 pressure (PETCO2) was measured by an infra red analyser. A pneumatic occlusion valve was mounted on the inspiratory line to determine inspiratory pressure 0.1 s after the onset inspiration (P0.1). Tidal volume (VT) and respiratory rate, were continuously monitored. Two to four times per minute, P0.1 was measured and the four precedent respiratory cycles were averaged to obtain mean ventilation (VE) and mean inspiratory flow (VT/TI) (RPM, Medical Graphics, St Paul, CA). Two respiratory cycles (the first just before and the second just after the occlusion) were then selected to measure instantaneous pressure and flow and calculate resistance. The circuit had a dead space equal to 135 ml and inspiratory and expiratory resistance equal to 1.29 cmH2O·l·sec, at flow until 2 l·sec. Progressive hyperoxic hypercapnia was obtained by Read’s method (Read, 1967) and progressive normocapnic hypoxia was obtained with Rebuck’s method (Rebuck and Campbell, 1974). During the progressive hypoxic test, CO2 scrubber on the expiratory line maintained constancy of end tidal CO2 pressure at the baseline values 95 mmHg. Transcutaneous oxygen saturation (SaO2) was continuously recorded with a finger probe connected to a pulse oxymeter (Ohmeda Biox 3700, Boulder, CO).
to accustom the subject and for lidocaine clearance. Measurements were obtained first during room air breathing, then during hypercapnia or hypoxia. When the subjects underwent the two challenges, another 30 min period was allowed for recuperation between the two tests. All recordings were made during exclusive nasal breathing. The challenges were continued until the subject opened their mouth or asked to stop because of discomfort.
2.4. Additional experiment: nasal resistance measurements In four subjects (DC, VE, XB, YL) we positioned a second catheter in the posterior nasopharynx just above the uvula, at 7–8 cm from the nostril to record oropharyngeal pressure. Nasal resistance was then determined in four subjects during hypercapnic challenge and in two during hypoxic challenge.
2.5. Statistical analysis Variations in data were expressed as mean9 S.D. Statistical analysis was performed using the SuperAnova® 4.5 software (Abacus Concept, Berkeley, CA) running on an Apple Macintosh computer. For each subject, slopes of VE/PETCO2, VT/TI/PETCO2, P0.1/PETCO2, VE/SaO2, VT/TI/SaO2 and P0.1/SaO2 were determined as an index of ventilatory drive. Variations in iUAR and eUAR as a function of changes in PETCO2 during the hypercapnic challenge and of SaO2 during hypoxic challenge were analysed by linear regression by the least-squares method. Comparisons between inspiratory and expiratory resistance recorded during room air breathing, hypercapnia or hypoxia, were done with a non-parametric test for paired data (Wilcoxon test). Variations were considered significant for P value B 0.05.
2.3. Procedures
3. Results
Subjects were placed in a semi-recumbent position, and were asked not to breathe through the mouth. A 30 min period was allowed between the setting of the catheter and the beginning of the test
3.1. Rebreathing tests Hypercapnic or hypoxic ventilatory responses were in the normal range for each subject. Slopes of
E. Verin et al. / Respiration Physiology 124 (2000) 35–42
VE/PETCO2, VT/TI/PETCO2, P0.1/ PETCO2, VE/SaO2, VT/TI/ SaO2 and P0.1/SaO2 are given in Table 1. During hypercapnic challenge, maximum PETCO2 was 5794 mmHg, maximum ventilation was 369 9 l·min. During hypoxic challenge, minimum SaO2 was 86 9 3% and maximum ventilation was 259 6 l·min.
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eUAR: PB 0.0001) and decreased as SaO2 decreased (iUAR and eUAR: PB 0.0001) (Fig. 1). Expiratory upper airway resistance was always lower than inspiratory during hypercapnic challenge (PB 0.0001) and during hypoxic challenge (PB 0.0001).
3.4. Nasal resistance 3.2. Base-line resistance During room air breathing, inspiratory baseline resistances were always higher than expiratory resistance (PB0.05) (mean inspiratory value for all the subjects =5.9 92.7 cmH2O·l − 1 sec − 1 (S.D.) vs 4.492.3 cmH2O·l − 1 sec − 1).
3.3. Resistance during hypercapnia and hypoxia Individually, in all the subjects, expiratory and inspiratory upper airway resistances decreased significantly during hypercapnic or hypoxic challenges (Table 2). When all the data were pooled, (reported to baseline value, to account for between-subject differences) inspiratory, as well as expiratory, upper airway resistances decreased as end tidal CO2 pressure increased (iUAR and
Table 2 Individual coefficients of the slopes of inspiratory upper airway (iUAR) and expiratory upper airway (eUAR)/PETCO2 (cmH2O·1−1 mmHg−1) during the hypercapnic challenge, and iUAR and eUAR/SaO2 (cmH2O·l−1 %−1) during the hypoxic challenge. In all cases, significant correlation between iUAR, eUAR and PETCO2 or SaO2 was found (Fig. 1) Subjects
AB AJ AT CT DC SB VE XB YL
Hypercapnic challenge
Hypoxic challenge
iUAR
eUAR
iUAR
eUAR
– −0.12* – −0.13c −0.65* −0.41* −1.20* −0.38* −0.40*
– −0.14§ – −0.93* −0.21* −0.30* −0.43§ −0.13* −0.38*
0.16c 0.10 c 0.47 c 0.44* – – 0.5* 0.25 c –
0.14c 0.08* 0.46* 0.24* – – 0.42* 0.12 c –
* PB0.05; c : PB0.01; §: PB0.001
In the four subjects studied, oropharyngeal resistance decreased during the hypercapnic and hypoxic challenges (PB 0.05).
4. Discussion Determining the factors affecting the maintenance of upper airway has gained major importance since Remmers et al. (1978) proposed that upper airway collapse occurs when the negative intraluminal pressure generated by the respiratory pump during inspiration is inadequately opposed by pharyngeal dilator muscle activation. In this study we demonstrated that like inspiratory upper airway resistance, expiratory upper airway resistance decreased during hypercapnic or hypoxic challenges. Before these results can be fully interpreted, several methodological procedures need to be considered. In our study hypopharyngeal pressures were measured with a bias-flow catheter. This method has been previously described by Hudgel (1986) and appears to be accurate in determining upper airway pressures. Topical anaesthesia could have modified UAR, since it provides an upper airway mecanoreceptor blockade, and modifies upper airway behaviour. In our study, only the nostrils were anaesthetised, but the subjects did not stop swallowing and a part of their pharynx could have been anaesthetised. Therefore, we chose to begin the experiment 30 min after the anaesthesia to eliminate a potential lidocaine effect. The rebreathing challenges were stopped when the subjects could no longer continue with exclusive nasal breathing and were obliged to open their mouth: indeed, opening the mouth is known
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E. Verin et al. / Respiration Physiology 124 (2000) 35–42
Fig. 1. Inspiratory and expiratory upper airway resistance changes in all subjects. (A) inspiratory (left) and expiratory (right) upper airway resistance during hypercapnia. (B) inspiratory (left) and expiratory (right) upper airway resistance during hypoxia. Upper airway resistance are reported to baseline value obtained during room air breathing for each subject. In all subjects, iUAR and eUAR decreased significantly as end tidal CO2 pressure (PETCO2) increased or as transcutaneous oxygen desaturation (SaO2) decreased.
to dramatically increase upper airway collapsibility (Meurice et al., 1996). Then, maximum ventilation at the end of the tests was lower than usually observed during conventional rebreathing challenges and may explain why the chemical stimulations remained in low ranges. In humans exclusive nasal breathing is tolerated until a switch which may vary between 35 and 45 l·min (Niinimaa et al., 1981). The maximum ventilation observed in our subjects were in this range of value. In all subjects inspiratory upper airway resistance was always greater than expiratory resistance, at baseline condition and during the both challenges. This phenomenon has already been described during room air breathing in healthy subjects and in snorers (Henke, 1998), but never during hypoxic or hypercapnic challenges. Upper airway patency is determined in part by the
difference between intraluminal and extraluminal pressure and the stiffness of the upper airway. This stiffness is largely determined by upper airway muscle activities. During inspiration, a negative intraluminal pressure is generated and potentially results in collapsing transmural pressure. During expiration, positive intraluminal pressure is generated, which generally prevents collapse of the upper airway. Decrease in inspiratory upper airway resistance with an increase in respiratory drive has already been demonstrated in awake healthy subjects. Inspiratory upper airway resistance decreased while VT/TI and P0.1 increased during hypercapnic (Se´rie`s et al., 1989) or during hypoxic challenges (Maltais et al., 1991). It has previously been demonstrated that there is a simultaneous EMG response of the upper airway dilator muscles and diaphragm during chemical respiratory stim-
E. Verin et al. / Respiration Physiology 124 (2000) 35–42
ulation: pharyngeal dilator muscle electromyographic activities (genioglossus and alae nasi) increased during hypoxia or hypercapnia (O8 nal et al., 1981a,b; Patrick et al., 1982). This could explain why the control of inspiratory upper airway opening is intimately linked to the regulation of breathing. We demonstrated that, like inspiratory upper airway resistance, expiratory resistance decreased during hypercapnic or hypoxic challenge. Several factors could explain such a phenomenon. First, increase in lung volume could have induced a decrease in upper airway resistance. In fact, Se´rie`s et al. have demonstrated that increase or decrease in lung volume could modify upper airway resistance (Se´rie`s et al., 1990). We did not monitor changes in functional residual capacity, which could increase during the hypercapnic or hypoxic test. However, this rise would have been of very small amplitude since high level of respiratory drive stimulations was not reached (Se´rie`s et al., 1989) and could not strongly influence upper airway resistance. Second, upper airway muscle activity could also play an important role. In spontaneously breathing cats, hyperoxic hypercapnia and normocapnic hypoxia lowered expiratory laryngeal resistance and hypocapnia increased expiratory laryngeal resistance (Bartlett, 1979). More recently, it has been demonstrated in humans that the response of tongue protudor (genioglossus) and retractors (styloglossus and hyoglossus) were co-activated under hypoxia or hypercapnia, in the early stage of inspiration (Mateika et al., 1999). The nasal region and hypopharynx could have a different response to chemical stimulation. Nevertheless, in the four subjects studied with an additional oropharyngeal catheter, we did not find a different behaviour in oropharyngeal resistance which decreased during hypoxic or hypercapnic tests, as previously reported for inspiratory resistance (Se´rie`s et al., 1989; Maltais et al., 1991). In conclusion, expiratory upper airway resistance was always lower than inspiratory upper airway resistance, and decreased during hypercapnic or hypoxic respiratory stimulations in healthy subjects. These results suggest a possible
41
significant role of central and peripheral chemoreceptors in determining expiratory upper airway patency.
Acknowledgements The authors thank Richard Medeiros for his valuable advice in editing the manuscript.
References Bartlett, D., Jr., 1979. Effects of hypercapnia and hypoxia on laryngeal resistance to airflow. Respir. Physiol. 37, 293 – 302. Dinh, L., Maltais, F., Se´rie`s, F., 1991. Influence of progressive and of transient hypoxia on upper airway resistance in normal humans. Am. Rev. Respir. Dis. 143, 1312 – 1316. Henke, K., 1998. Upper airway muscle activity and upper airway resistance in young adults during sleep. J. Appl. Physiol. 84, 486 – 491. Hudgel, D.W., 1986. Variable site of airway narrowing among obstructive sleep apnea patients. J. Appl. Physiol. 61, 1403 – 1409. Lofaso, F., Lorino, A.M., Fodil, R., D’Ortho, M.P., Isabey, D., Lorino, H., Goldenberg, F., Harf, A., 1998. Heavy snoring with upper airway resistance syndrome may induce intrinsic positive end-expiratory pressure. J. Appl. Physiol. 85, 860 – 866. Maltais, F., Dinh, F., Cormier, Y., Se´rie`s, F., 1991. Changes in upper airway resistance during progressive normocapnic hypoxia in normal men. J. Appl. Physiol. 70, 548 – 553. Mateika, J., Millrood, D.L., Kim, J., Rodriguez, H.P., Samara, G.J., 1999. Response of human tongue protrudor and retractors to hypoxia and hypercapnia. Am. J. Respir. Crit. Care Med. 160, 1976 – 1982. Meurice, J.C., Marc, I., Carrier, G., Se´rie`s, F., 1996. Effects of mouth opening on upper airway collapsibility in normal sleeping subjects. Am. J. Respir. Crit. Care Med. 153, 255 – 259. Niinimaa, V., Cole, P., Mintz, S., Shephard, R.J., 1981. Oronasal distribution of respiratory airflow. Respir. Physiol. 43, 69 – 75. O8 nal, E., Lopata, M., O’Connor, T.D., 1981a. Diaphragmatic and genioglossal electromyogram responses to CO2 rebreathing in humans. J. Appl. Physiol. 50, 1052 – 1055. O8 nal, E., Lopata, M., O’Connor, T.D., 1981b. Diaphragmatic and genioglossal electromyogram responses to isocapnic hypoxia in humans. Am. Rev. Respir. Dis. 124, 215 – 217. Patrick, B.G., Strohl, K.P., Rubin, S.B., Altose, M.D., 1982. Upper airway and diaphragm muscle responses to chemical stimulation and loading. J. Appl. Physiol. 53, 1133 – 1137.
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Read, D., 1967. A clinical method for assessing the ventilatory response to carbon dioxide. Aust. Ann. Med. 16, 20–32. Rebuck, A.S., Campbell, E.M.J., 1974. A clinical method for assessing the ventilatory response to hypoxia. Am. Rev. Respir. Dis. 109, 345–350. Remmers, J.E., Degroot, W.J., Sauerland, E.K., Anch, A.M., 1978. Pathogenesis of upper airway occlusion during sleep. J. Appl. Physiol. 44, 931–938. Sanders, M.H., Rogers, R.M., Pennock, B.E., 1985. Prolonged expiratory phase in sleep apnea. A unifying hypothesis. Am. Rev. Respir. Dis. 131, 401–408.
.
Se´rie`s, F., Cormier, Y., Desmeules, M., La Forge, J., 1989. Influence of respiratory drive on upper airway resistance in normal men. J. Appl. Physiol. 66, 1242 – 1249. Se´rie`s, F., Cormier, Y., Desmeules, M., 1990. Influence of passive changes in lung volume on upper airways. J. Appl. Physiol. 68, 2159 – 2164. Stanescu, D., Kostianev, S., Sanna, A., Liistro, G., Veriter, C., 1996. Expiratory flow limitation during sleep in heavy snorers and obstructive sleep apnoea patients. Eur. Respir. J. 9, 2116 – 2121.
Upper airway resistance during progressive hypercapnia and progressive hypoxia in normal awake subjects Eric Verin a,*, Catherine Tardif a, Jean Paul Marie b, Xavier Buffet b, Yann Lacoume a, Pascal Delapille a, Pierre Pasquis a a
Ser6ice de Physiologie Respiratoire et Sporti6e, CHU de Rouen, Hopital de Bois Guillaume-147 A6enue du Mare´chal Juin, 76230 Bois Guillaume, France b Ser6ice d’ORL et chirurgie cer6ico faciale, CHU de Rouen, Hopital Charles Nicolle-1 rue de Germont 76031, Rouen Cedex, France Accepted 28 August 2000
Abstract Ventilatory motor output is known to influence the upper airway. Although inspiratory upper airway resistance decreases during progressive hypoxia or hypercapnia, the effects of hypoxia and hypercapnia on expiratory upper airway resistance remain unknown. In the present study, we attempted to examine whether the expiratory and the inspiratory upper airway resistances were modified in the same way by progressive hyperoxic hypercapnia or by progressive normocapnic hypoxia. Nine healthy subjects (five males, four females, 33 9 9 years) participated in the study. Inspiratory upper airway (iUAR) and expiratory upper airway resistances (eUAR) were calculated at flow 300 ml s − 1. Both resistances were obtained during a baseline period and during progressive hyperoxic hypercapnia or progressive normocapnic hypoxia. In all subjects, iUAR and eUAR decreased significantly during hypercapnic or hypoxic challenge (PB0.05). eUAR was always lower than iUAR during hypercapnic challenge (PB 0.0001) and during hypoxic challenge (P B0.0001). The authors conclude that expiratory upper airway resistance, as with inspiratory resistance, decreases during progressive hypercapnia or during progressive hypoxia. Pharyngeal dilator or constrictor muscle activities may be implicated. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Control of breathing; Respiratory drive; Hypercapnia; Progressive; Airway resistance; Hypoxia; Mammals; Humans; Upper airways; Resistance
1. Introduction
* Corresponding author. Tel.: +33-232-889222; fax: + 33232-889139. E-mail address: [email protected] (E. Verin).
In both animals and humans, the upper airway plays a role in determining the breathing pattern during inspiration and expiration. In humans, during inspiration, activation of diaphragm and upper airway dilator muscles is closely synchro-
0034-5687/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 0 3 4 - 5 6 8 7 ( 0 0 ) 0 0 1 8 9 - 4
36
E. Verin et al. / Respiration Physiology 124 (2000) 35–42
nised, and like the diaphragm, upper airway dilator muscle activities increase during hypercapnic and hypoxic stimulations (O8 nal et al., 1981a,b). This upper airway dilator muscle activation permits the upper airway to resist collapsing during diaphragmatic contraction. In sleep apnea syndrome, airway abnormalities occur both during expiratory and inspiratory phases of ventilation. Inspiratory anomalies (apnea or hypopnea) were first discovered and explored by Remmers et al. (1978). However, more recent studies have demonstrated that narrowing of the upper airway can also occur during expiration. Increased expiratory resistance (Sanders et al., 1985) and prolonged expiratory air flow (Stanescu et al., 1996) are associated with the breath preceding the initial occluded inspiratory effort in occlusive apnea. Lofaso et al. (1998) have demonstrated that an increase in expiratory resistance is of a similar magnitude as the increase in inspiratory resistance. It also promotes dynamic hyperinflation, increases inspiratory work and could participate in CO2 retention or O2 deprivation during sleep. Therefore, a decrease in upper airway resistance during hypercapnia and hypoxia should facilitate ventilation. In healthy awake subjects, inspiratory upper airway resistance has previously been demonstrated to decrease during progressive hyperoxic hypercapnic challenge and progressive normocapnic hypoxic challenge (Se´rie`s et al., 1989; Dinh et al., 1991; Maltais et al., 1991). In the present study, we attempted to examine if expiratory upper resistance was also modified by progressive hyperoxic hypercapnia or by progressive normocapnic hypoxia, in healthy awake subjects.
2. Method
2.1. Subjects Nine healthy subjects (five males, four females) participated in the study. Seven subjects underwent hypercapnic challenge, six subjects underwent hypoxic challenge (four subjects underwent the two challenges). Their mean age was 3399 years with a normal body mass index (229 2 kg
m − 2) (Table 1). No subjects were on medication or complained of symptoms, which suggest of sleep apnoea syndrome. Each subject volunteered to participate in the study and gave their informed consent prior to participating in the study.
2.2. Measurements We independently measured upper airway resistance and respiratory response to chemical stimulations, with two different systems.
2.2.1. Upper airway resistance
2.2.1.1. Nasal flow. A tightly fitting translucent mask (continuous positive airway pressure mask, Respironics, Murrisville, PA) was placed over the nose, connected to a Fleish n°.3 pneumotachograph (Hans Rudolph, Kansas City, MO) to measure instantaneous flow. 2.2.1.2. Hypopharyngeal pressure. Hypopharyngeal pressure, or supralaryngeal pressure, was measured with a catheter (XRO feeding tube, 50 cm length, external diameter=2.4 mm; internal diameter=1.4 mm, Vygon®, Ecouen, France) connected to a Valydine MP 45-1 differential pressure transducer (9100 cmH2O, Valydine, Northridge, CA). It was passed through the mask and introduced into one nostril, after topical anaesthesia (lidocaine spray 5%) and lubrication of the catheter (lidocaine gel 2%). The tip was inserted into the lower part of the hypopharynx, as far down as the patient could tolerate without gag or discomfort in swallowing (189 2 cm from the nostrils). In this position, it was posterior to the epiglottis (Hudgel, 1986). The side of the catheter was perforated with two holes near its sealed tip. To assure upper airway catheter patency and keep the catheter free of secretion, equal bias flow of 0.1·l·min of compressed air was passed through each catheter. Pressure measurement was referenced to the mask. Pressure and flow were recorded on an electrostatic system Gould ES 2000® (Gould Instrument System, Valley View, OH).
47 25 24 44 22 28 31 42 31 33 9
Age years
F M M F F F M M M
Sex
22 20 25 21 21 25 25 20 19 22 2
BMI kg m−2
– 1.25 – 1.05 0.87 0.72 1.08 1.13 1.88 1.14 0.37
VE/PETCO2 l min−1 mmHg−1 – 0.03 – 0.02 0.06 0.02 0.04 0.04 0.09 0.04 0.03
VT/TI/PETCO2 l s−1 mmHg−1
n.a. – 0.34 0.68 0.36 0.66 0.25 0.24 0.42 0.20
P0.1/PETCO2 cmH2O·mmHg−1
−1.20 −0.88 −0.62 –0.71 – – −1.70 −0.58 – −0.95 0.43
VE/SaO2 min−1 %−1
n.a.: data non available. Seven subjects underwent an hypercapnic challenge and six subjects an hypoxic challenge (four subjects underwent the two challenges).
a
AB AJ AT CT DC SB VE XB YL Mean S.D.
Subjects
Table 1 Anthropometric data and indices of ventilatory drive of the nine subjectsa
−0.06 −0.08 −0.03 −0.04 – – −0.06 −0.05 – −0.05 0.02
VT/TI/SaO2 l sec−1 %−1
−0.44 −0.70 −0.25 −0.35 – – −0.60 −0.14 – −0.41 0.21
P0.l/SaO2 cmH2O %−1
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2.2.1.3. Upper airway resistance. Because there is a non-linear relationship between airflow and pressure, inspiratory and expiratory resistances were calculated at flow 300 ml·sec. Inspiratory and expiratory upper airway resistances were calculated by the ratio of the pressure to the flow (respectively iUAR and eUAR). 2.2.2. Hypercapnic challenges and hypoxic challenges A 5 l bag, connected to inspiratory and expiratory lines completed the rebreathing circuit. A Hans Rudolph effort valve was connected to a pneumotachograph n°3 (Hans Rudolph, Kansas City, MO), to separate the inspiratory and the expiratory lines. End tidal CO2 pressure (PETCO2) was measured by an infra red analyser. A pneumatic occlusion valve was mounted on the inspiratory line to determine inspiratory pressure 0.1 s after the onset inspiration (P0.1). Tidal volume (VT) and respiratory rate, were continuously monitored. Two to four times per minute, P0.1 was measured and the four precedent respiratory cycles were averaged to obtain mean ventilation (VE) and mean inspiratory flow (VT/TI) (RPM, Medical Graphics, St Paul, CA). Two respiratory cycles (the first just before and the second just after the occlusion) were then selected to measure instantaneous pressure and flow and calculate resistance. The circuit had a dead space equal to 135 ml and inspiratory and expiratory resistance equal to 1.29 cmH2O·l·sec, at flow until 2 l·sec. Progressive hyperoxic hypercapnia was obtained by Read’s method (Read, 1967) and progressive normocapnic hypoxia was obtained with Rebuck’s method (Rebuck and Campbell, 1974). During the progressive hypoxic test, CO2 scrubber on the expiratory line maintained constancy of end tidal CO2 pressure at the baseline values 95 mmHg. Transcutaneous oxygen saturation (SaO2) was continuously recorded with a finger probe connected to a pulse oxymeter (Ohmeda Biox 3700, Boulder, CO).
to accustom the subject and for lidocaine clearance. Measurements were obtained first during room air breathing, then during hypercapnia or hypoxia. When the subjects underwent the two challenges, another 30 min period was allowed for recuperation between the two tests. All recordings were made during exclusive nasal breathing. The challenges were continued until the subject opened their mouth or asked to stop because of discomfort.
2.4. Additional experiment: nasal resistance measurements In four subjects (DC, VE, XB, YL) we positioned a second catheter in the posterior nasopharynx just above the uvula, at 7–8 cm from the nostril to record oropharyngeal pressure. Nasal resistance was then determined in four subjects during hypercapnic challenge and in two during hypoxic challenge.
2.5. Statistical analysis Variations in data were expressed as mean9 S.D. Statistical analysis was performed using the SuperAnova® 4.5 software (Abacus Concept, Berkeley, CA) running on an Apple Macintosh computer. For each subject, slopes of VE/PETCO2, VT/TI/PETCO2, P0.1/PETCO2, VE/SaO2, VT/TI/SaO2 and P0.1/SaO2 were determined as an index of ventilatory drive. Variations in iUAR and eUAR as a function of changes in PETCO2 during the hypercapnic challenge and of SaO2 during hypoxic challenge were analysed by linear regression by the least-squares method. Comparisons between inspiratory and expiratory resistance recorded during room air breathing, hypercapnia or hypoxia, were done with a non-parametric test for paired data (Wilcoxon test). Variations were considered significant for P value B 0.05.
2.3. Procedures
3. Results
Subjects were placed in a semi-recumbent position, and were asked not to breathe through the mouth. A 30 min period was allowed between the setting of the catheter and the beginning of the test
3.1. Rebreathing tests Hypercapnic or hypoxic ventilatory responses were in the normal range for each subject. Slopes of
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VE/PETCO2, VT/TI/PETCO2, P0.1/ PETCO2, VE/SaO2, VT/TI/ SaO2 and P0.1/SaO2 are given in Table 1. During hypercapnic challenge, maximum PETCO2 was 5794 mmHg, maximum ventilation was 369 9 l·min. During hypoxic challenge, minimum SaO2 was 86 9 3% and maximum ventilation was 259 6 l·min.
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eUAR: PB 0.0001) and decreased as SaO2 decreased (iUAR and eUAR: PB 0.0001) (Fig. 1). Expiratory upper airway resistance was always lower than inspiratory during hypercapnic challenge (PB 0.0001) and during hypoxic challenge (PB 0.0001).
3.4. Nasal resistance 3.2. Base-line resistance During room air breathing, inspiratory baseline resistances were always higher than expiratory resistance (PB0.05) (mean inspiratory value for all the subjects =5.9 92.7 cmH2O·l − 1 sec − 1 (S.D.) vs 4.492.3 cmH2O·l − 1 sec − 1).
3.3. Resistance during hypercapnia and hypoxia Individually, in all the subjects, expiratory and inspiratory upper airway resistances decreased significantly during hypercapnic or hypoxic challenges (Table 2). When all the data were pooled, (reported to baseline value, to account for between-subject differences) inspiratory, as well as expiratory, upper airway resistances decreased as end tidal CO2 pressure increased (iUAR and
Table 2 Individual coefficients of the slopes of inspiratory upper airway (iUAR) and expiratory upper airway (eUAR)/PETCO2 (cmH2O·1−1 mmHg−1) during the hypercapnic challenge, and iUAR and eUAR/SaO2 (cmH2O·l−1 %−1) during the hypoxic challenge. In all cases, significant correlation between iUAR, eUAR and PETCO2 or SaO2 was found (Fig. 1) Subjects
AB AJ AT CT DC SB VE XB YL
Hypercapnic challenge
Hypoxic challenge
iUAR
eUAR
iUAR
eUAR
– −0.12* – −0.13c −0.65* −0.41* −1.20* −0.38* −0.40*
– −0.14§ – −0.93* −0.21* −0.30* −0.43§ −0.13* −0.38*
0.16c 0.10 c 0.47 c 0.44* – – 0.5* 0.25 c –
0.14c 0.08* 0.46* 0.24* – – 0.42* 0.12 c –
* PB0.05; c : PB0.01; §: PB0.001
In the four subjects studied, oropharyngeal resistance decreased during the hypercapnic and hypoxic challenges (PB 0.05).
4. Discussion Determining the factors affecting the maintenance of upper airway has gained major importance since Remmers et al. (1978) proposed that upper airway collapse occurs when the negative intraluminal pressure generated by the respiratory pump during inspiration is inadequately opposed by pharyngeal dilator muscle activation. In this study we demonstrated that like inspiratory upper airway resistance, expiratory upper airway resistance decreased during hypercapnic or hypoxic challenges. Before these results can be fully interpreted, several methodological procedures need to be considered. In our study hypopharyngeal pressures were measured with a bias-flow catheter. This method has been previously described by Hudgel (1986) and appears to be accurate in determining upper airway pressures. Topical anaesthesia could have modified UAR, since it provides an upper airway mecanoreceptor blockade, and modifies upper airway behaviour. In our study, only the nostrils were anaesthetised, but the subjects did not stop swallowing and a part of their pharynx could have been anaesthetised. Therefore, we chose to begin the experiment 30 min after the anaesthesia to eliminate a potential lidocaine effect. The rebreathing challenges were stopped when the subjects could no longer continue with exclusive nasal breathing and were obliged to open their mouth: indeed, opening the mouth is known
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Fig. 1. Inspiratory and expiratory upper airway resistance changes in all subjects. (A) inspiratory (left) and expiratory (right) upper airway resistance during hypercapnia. (B) inspiratory (left) and expiratory (right) upper airway resistance during hypoxia. Upper airway resistance are reported to baseline value obtained during room air breathing for each subject. In all subjects, iUAR and eUAR decreased significantly as end tidal CO2 pressure (PETCO2) increased or as transcutaneous oxygen desaturation (SaO2) decreased.
to dramatically increase upper airway collapsibility (Meurice et al., 1996). Then, maximum ventilation at the end of the tests was lower than usually observed during conventional rebreathing challenges and may explain why the chemical stimulations remained in low ranges. In humans exclusive nasal breathing is tolerated until a switch which may vary between 35 and 45 l·min (Niinimaa et al., 1981). The maximum ventilation observed in our subjects were in this range of value. In all subjects inspiratory upper airway resistance was always greater than expiratory resistance, at baseline condition and during the both challenges. This phenomenon has already been described during room air breathing in healthy subjects and in snorers (Henke, 1998), but never during hypoxic or hypercapnic challenges. Upper airway patency is determined in part by the
difference between intraluminal and extraluminal pressure and the stiffness of the upper airway. This stiffness is largely determined by upper airway muscle activities. During inspiration, a negative intraluminal pressure is generated and potentially results in collapsing transmural pressure. During expiration, positive intraluminal pressure is generated, which generally prevents collapse of the upper airway. Decrease in inspiratory upper airway resistance with an increase in respiratory drive has already been demonstrated in awake healthy subjects. Inspiratory upper airway resistance decreased while VT/TI and P0.1 increased during hypercapnic (Se´rie`s et al., 1989) or during hypoxic challenges (Maltais et al., 1991). It has previously been demonstrated that there is a simultaneous EMG response of the upper airway dilator muscles and diaphragm during chemical respiratory stim-
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ulation: pharyngeal dilator muscle electromyographic activities (genioglossus and alae nasi) increased during hypoxia or hypercapnia (O8 nal et al., 1981a,b; Patrick et al., 1982). This could explain why the control of inspiratory upper airway opening is intimately linked to the regulation of breathing. We demonstrated that, like inspiratory upper airway resistance, expiratory resistance decreased during hypercapnic or hypoxic challenge. Several factors could explain such a phenomenon. First, increase in lung volume could have induced a decrease in upper airway resistance. In fact, Se´rie`s et al. have demonstrated that increase or decrease in lung volume could modify upper airway resistance (Se´rie`s et al., 1990). We did not monitor changes in functional residual capacity, which could increase during the hypercapnic or hypoxic test. However, this rise would have been of very small amplitude since high level of respiratory drive stimulations was not reached (Se´rie`s et al., 1989) and could not strongly influence upper airway resistance. Second, upper airway muscle activity could also play an important role. In spontaneously breathing cats, hyperoxic hypercapnia and normocapnic hypoxia lowered expiratory laryngeal resistance and hypocapnia increased expiratory laryngeal resistance (Bartlett, 1979). More recently, it has been demonstrated in humans that the response of tongue protudor (genioglossus) and retractors (styloglossus and hyoglossus) were co-activated under hypoxia or hypercapnia, in the early stage of inspiration (Mateika et al., 1999). The nasal region and hypopharynx could have a different response to chemical stimulation. Nevertheless, in the four subjects studied with an additional oropharyngeal catheter, we did not find a different behaviour in oropharyngeal resistance which decreased during hypoxic or hypercapnic tests, as previously reported for inspiratory resistance (Se´rie`s et al., 1989; Maltais et al., 1991). In conclusion, expiratory upper airway resistance was always lower than inspiratory upper airway resistance, and decreased during hypercapnic or hypoxic respiratory stimulations in healthy subjects. These results suggest a possible
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significant role of central and peripheral chemoreceptors in determining expiratory upper airway patency.
Acknowledgements The authors thank Richard Medeiros for his valuable advice in editing the manuscript.
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