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Division of Respiratory Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W8
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Krishnan, Bharath S., Ron E. Clemens, Trevor A. Zintel,
Martin J. Stockwell, and Charles G. Gallagher. Ventilatory response to helium-oxygen breathing during exercise: effect of airway
anesthesia. J. Appl. Physiol. 83(1):
82-88, 1997.
The substitution of a normoxic helium mixture
(HeO2) for room air (Air) during exercise results in a sustained hyperventilation, which is present even
in the first breath. We hypothesized that this response is dependent on
intact airway afferents; if so, airway anesthesia (Anesthesia) should
affect this response. Anesthesia was administered to the upper airways
by topical application and to lower central airways by aerosol
inhalation and was confirmed to be effective for over 15 min. Subjects
performed constant work-rate exercise (CWE) at 69 ± 2 (SE) % maximal work rate on a cycle ergometer on three separate days: twice
after saline inhalation (days 1 and
3) and once after Anesthesia
(day 2). CWE commenced after a brief
warm-up, with subjects breathing Air for the first 5 min (Air-1),
HeO2 for the next 3 min, and Air
again until the end of CWE (Air-2). The resistance of the breathing
circuit was matched for Air and
HeO2. Breathing
HeO2 resulted in a small but
significant increase in minute ventilation
(
I) and
decrease in alveolar PCO2 in both the
Saline (average of 2 saline tests; not significant) and Anesthesia
tests. Although Anesthesia had no effect on the sustained
hyperventilatory response to HeO2
breathing, the
I transients
within the first six breaths of
HeO2 were significantly attenuated
with Anesthesia. We conclude that the
I response to HeO2 is not simply due to a
reduction in external tubing resistance and that, in humans, airway
afferents mediate the transient but not the sustained hyperventilatory
response to HeO2 breathing during
exercise.
heliox hyperventilation
INTRODUCTION THE SUBSTITUTION OF A NORMOXIC helium-oxygen mixture
(HeO2) for room air (Air) during
exercise causes an increase in minute ventilation
( We also examined the effects of external tubing resistance on the
response to HeO2 breathing because
HeO2 reduces external tubing
resistance, as well as internal airway resistance. With Air breathing, an increase in external resistance causes a decrease in
MATERIALS AND METHODS
I) that is
evident in the first breath (11, 15, 35). The mechanisms underlying the
ventilatory response to HeO2 breathing are unclear. Because of its reduced density,
HeO2 reduces turbulence and
therefore flow resistance in the airways, especially in the upper
airways (25). It has been suggested that the respiratory adaptations to
HeO2 breathing may indicate a
reflex effect (15). Ward et al. (35) have suggested that the altered
activation of irritant or other airway receptors might contribute to
the hyperventilation with HeO2.
Afferent information arising from numerous receptors (sensitive to
flow, pressure, temperature, and
CO2) in the larynx (33) and the
tracheobronchial tree (31) has been shown to influence ventilatory
control, in both humans (10, 22) and animals (31). Both
topical (10, 21) and inhaled aerosol anesthesia (10, 22) have been used
effectively in humans for reversible blockade of these vagally mediated
afferents. We therefore examined the effects of airway anesthesia
(Anesthesia) on the transient and sustained
I response to
HeO2 breathing during exercise in
normal humans. Because the reduction in turbulent flow with
HeO2 breathing during exercise is
most marked in the upper (extrathoracic) and major intrathoracic
airways (25), we combined two methods of Anesthesia administration (10,
21, 22) to target these sites, as has been done in previous studies (18).
I
during exercise (9). It is therefore possible that the I
response to HeO2 breathing is a
consequence of the change in external resistive load rather than the
change in internal load. The external equipment resistance was
therefore matched for both Air and
HeO2 in this study (8).
5 (leastmost) scale
in each subject. The single-breath vital capacity inhalation (at 1 l/s)
maneuver (34) was then used to assess the subjects' cough threshold
for nebulized citric acid solutions of doubling concentration (0, 1, 2, 4 . . . 32%). At the end of every 2 min after Anesthesia was
administered by using the technique described above, each subject was
asked to grade these same sensations on the same scale as before. At
the end of every 5 min after Anesthesia administration, each subject underwent a nebulized citric acid inhalation challenge (34) at the
previously determined threshold concentration.
Exercise protocol.
On day 2, each subject performed
maximal incremental exercise to exhaustion while breathing Air, to
measure peak work rate (Wmax; 325 ± 16 W). On days
3-5, each subject performed CWE at ~69 ± 2%
Wmax (range 160-290 W, 64-77% Wmax) for 13 min. The CWE protocol on all occasions consisted of a brief warm-up exercise at 75 W
(range 19-30% Wmax) for 1 min, after which the work rate was
abruptly increased to the predetermined level for each subject. The
inspirate was Air during both the warm-up period and the first 5 min of
CWE (Air-1), at the end of which the inspirate was abruptly switched
(during expiration) to HeO2. The
subject breathed HeO2 for the next
3 min, and the inspirate was then switched back (during expiration) to
Air. Each subject continued to exercise while breathing Air for the
next 5 min (Air-2) or until exhaustion (whichever came first). On
days 3 and
5 (Control studies), the subjects
inhaled nebulized normal saline (5 ml of 0.9% solution, no
preservatives) just before the start of CWE (Saline-1, Saline-2) by
using the same inhalation pattern as that used with Anesthesia
administration. On day 4, Anesthesia
was administered just before the start of CWE in a fashion identical to
that described earlier. An identical CWE protocol was used on all three
(Saline-1, Saline-2, Anesthesia) occasions. One subject completed the
first minute of exercise in the Air-2 period on all three occasions,
and another subject stopped exercise immediately after the start of the
Air-2 period on the Anesthesia (day
4) test day. However, 9 of the 11 subjects completed
the 13 min of CWE (Air-1, HeO2,
Air-2) on all the three days.
Exercise equipment and measurements.
Both the incremental and constant work rate exercise tests were
conducted on an electrically braked cycle ergometer (Godart, Bilthoven,
Holland). The breathing apparatus consisted of a two-way non-rebreathing Y valve (dead space 115 ml, Hans Rudolph 2700, Kansas
City, MO) connected by short tubing (11/4" inner diameter) to
inspiratory and expiratory pneumotachographs (Fleisch no. 3), each of
which was connected to a two-way (switching) valve. These silent valves
were used to manually switch the inspiratory and expiratory limbs from
Air to HeO2 and vice versa,
without any disturbance to the exercising subject. Because it was
possible that the hyperventilatory effects of
HeO2 breathing may be due, in
part, to its unloading of the external tubing resistance, we took care
to match the flow resistance of the breathing circuit for both Air and
HeO2 before the study by using
methods employed by DeWeese et al. (8) at rest. By adding appropriate
fixed resistances to the HeO2
ports of the switching valves (on both the inspiratory and expiratory
limbs), we were able to match the flow resistances of both the
inspiratory and expiratory limbs of the breathing circuit for Air and
HeO2. Table
1 summarizes the flow ranges through which
the resistances of the inspiratory and expiratory limbs of the
breathing circuit (in both Air and HeO2) were matched. Both Air and
HeO2 were warmed and humidified and delivered from large meteorological balloon reservoirs that were
concealed from the subjects' direct view. With the aid of inspiratory
and expiratory flow sensors, one investigator was able to switch the
inspirate from Air to HeO2 (and
back again) at the appropriate phase of the breathing cycle and
exercise periods. None of the subjects was aware of any of these
switches, which were made from behind a screen.
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), volume (V),
CO2,
SaO2, and ECG were recorded continuously
on an 8-channel strip-chart recorder (Gould) and digitized. Data
analysis was performed on a computer that measured
inspiratory (TI), expiratory
(TE), and total
(TT) breath durations and
tidal volume (VT) for all
valid breaths during exercise (those interrupted by cough
and/or swallowing were identified and not included).
I was
derived from averaged VT and
breathing frequency (f ). Appropriate flow correction factors based
on calibrations before and after exercise were used to
correct during the
HeO2 periods. Because the mass
spectrometer was being calibrated (with the appropriate gas standard)
during the first 15 s of the minute immediately after the gas
transitions (HeO2, Air-2), the
CO2 data during these periods were
unavailable for analysis. However, all other variables were analyzed
during these periods. All the other data were collected on a
breath-by-breath basis throughout exercise and were used in data
analysis. With the use of previously described techniques (36),
time-weighted mean alveolar PCO2
,CO2)
was estimated from the averaged breath-by-breath airway
PCO2 signal for each minute of exercise.
,CO2
thus derived has been shown to accurately estimate arterial
PCO2 during exercise (36).
Data from the two Saline tests (Saline-1, Saline-2; not significant)
were averaged (Saline) in each subject for comparison with Anesthesia
data. To study steady-state effects, data from the last minute of Air-1
were averaged with data from the first minute of Air-2 for comparison
with the average data from the second minute of
HeO2. A paired
t-test (2-tailed) was used to detect
differences between Air and HeO2,
as well as between Saline and Anesthesia. To study the effects of
Anesthesia on the breath-by-breath effects of
HeO2,
I data from
the last 10 breaths in Air-1, first 6 breaths in
HeO2, and average
I data from
the second minute of HeO2 were
analyzed with a two-factor (gas, Anesthesia) repeated-measures analysis
of variance design. Significant breath-by-breath effects of
HeO2 on
I (in both
the Saline and Anesthesia tests) were then compared with Air in a
Dunnett's comparison procedure (Control group, Air-1). A
P < 0.05 was accepted as
significant.
RESULTS
5, leastmost) of the subjective sensations in
the mouth (2.8 ± 0.2), in the throat (2.5 ± 0.2), increased tolerance to blunt pharyngeal probing (2.2 ± 0.3), and gag reflex (2.5 ± 0.4), as well as persistent difficulty in swallowing (2.5 ± 0.2). These results are consistent with those from another study in this laboratory, in which subjects showed significant residual Anesthesia after exercise (18).
Effect of Anesthesia on hyperventilatory response to
HeO2.
Figure 1 shows group mean (±SE)
I, VT, f, and
,CO2
data during warm-up exercise [baseline values
(0)] and during the Air-1,
HeO2, and Air-2 periods during
CWE. Each point represents all valid data averaged over 1 min. As shown
in previous studies during CWE (6, 20),
I increased
rapidly in the first 3-4 min at the start of CWE and continued to
increase slowly throughout CWE. Most of the increase in
I was as a
result of an increase in f because
VT leveled off after the initial
increase in the first 2 min of CWE. There was a significant increase in
I and a fall
in ,CO2
after the switch to HeO2 as the
inspirate, and this hyperventilation persisted throughout the
HeO2 period. On the switch back to
Air (Air-2), however, there was a fall in I and an
increase in
,CO2
after which I increased (and
,CO2
fell) gradually until end exercise. The magnitude of increase in
I (~4 l/min;
Table 2) and fall in
,CO2 (~1.5 Torr) with HeO2 breathing,
although small, was significant (2-tailed
t-test) in both the Saline and
Anesthesia tests (Table 2). This modest increase in
I with
HeO2 breathing was due to a
significant increase in f because
HeO2 breathing did not alter VT significantly.
HeO2 breathing also resulted in a
small but significant fall in the inspiratory duty cycle
(TI / TT)
and a small but significant increase in
SaO2. However, as both Fig. 1 and Table
2 reveal, Anesthesia had no effect on the hyperventilatory response to
HeO2 breathing during CWE.
I), tidal
volume (VT), breathing
frequency (f), and estimated mean alveolar
PCO2 (P
)
during constant work rate exercise (CWE) in saline (Saline;
A) and airway anesthesia
(Anesthesia; B) tests. Each point
represents average data over each minute from 9 subjects who breathed
air during a warm-up period and the first 5 min of exercise (Air-1;
) and then were switched to
HeO2 as inspirate (
).
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I transients with
HeO2.
The effect of Anesthesia on the immediate increase in
I on the
switch to HeO2 is shown in Fig.
2. The averaged data from the last 10 breaths in Air-1 period (Saline vs. Anesthesia; not significant)
represent the baseline (0) values. Data are shown as the increase in
I
(
I in Fig.
2; see also Fig. 3) in the first six breaths of
HeO2 and in the second minute of
HeO2 breathing. In the Saline
test, I
increased immediately with HeO2
breathing, and almost all the increase in
I occurred by
the second breath. With Anesthesia, there was a noticeable attenuation
of this transient increase in
I in the first
five to six breaths of HeO2, but this effect was not present in the second minute of
HeO2.
I
(I;
HeO2 
Air) at
Air-1HeO2 transition in
Saline () and Anesthesia () tests. Data from first 6 breaths in
HeO2 and averaged data from 2nd
minute of HeO2 are shown. Averaged
data from last 10 breaths in Air-1 period represent baseline Air (
)
values. * Significantly different from Air [analysis of
variance (ANOVA)], P < 0.05.
I in 2nd
breath of HeO2
(A) and in 2nd minute of
HeO2 breathing
(B) in Saline compared with
Anesthesia tests. , Individual subject
(n = 11) responses; bar, group mean
responses. Group mean data (±SE) are indicated in parentheses below
labels. * Data significantly different from 0. A, Saline
vs. Anesthesia, P < 0.05 by ANOVA; B, Saline
vs. Anesthesia, NS.
Figure 3 summarizes the effects of Anesthesia on the transient increase in
I in the
second breath of HeO2 and in the
second minute of HeO2 in all
subjects. Increases in
I
(HeO2 Air) data in the
Saline test are compared with those in the Anesthesia test in each
subject. Ten of the 11 subjects had a smaller increase in
I in the
second breath of HeO2 after
Anesthesia than with Saline, and this difference was statistically
significant. This effect of Anesthesia, however, did not continue into
the second minute of HeO2
breathing.
DISCUSSION
The major findings of this study are 1) the immediate but not the sustained hyperventilation due to HeO2 is attenuated by airway anesthesia; and 2) HeO2 causes hyperventilation when the reduction in tubing resistance due to HeO2 is prevented; therefore, the HeO2 hyperventilation is not simply due to a change in external resistive load.
Previous studies. It has been shown that the substitution of HeO2 for Air results in an immediate and sustained increase inI (11, 15, 35). The magnitude of the
HeO2-induced hyperventilation
during exercise varies significantly among different studies but is
greatest at high levels of
I (2, 7, 30).
As emphasized by Ward et al. (35) and Pan et al. (27), this increase in
I is
attenuated by the resulting fall in arterial
PCO2. The increase in
I with
HeO2 has been attributed to its
physical properties; because of its lower density than air,
HeO2 reduces turbulence in
airways, primarily large airways, where airflow is turbulent (25). This
changes the distribution of resistance among different parts of the
airways, reduces total airway resistance (23), and results in
respiratory muscle unloading, i.e., respiratory muscles have to
generate less pressure for a given
I (15, 23).
However, respiratory muscle unloading by pressure-assist at the mouth
(38) causes little or no increase in
I during heavy
exercise (12, 20). Therefore, as reviewed elsewhere (6, 12, 20), the
hyperventilation with HeO2 is
probably not a consequence of respiratory muscle unloading per se. This is supported by the finding that the
I response to
HeO2 is unaffected by diaphragm
deafferentation (11). The hyperventilation may be related to the airway
effects of HeO2 (6, 11, 15, 35). The average rate of rise of the diaphragm EMG falls immediately when
HeO2 is substituted for room air
in exercising humans and ponies (11, 15). It has therefore been
suggested that the respiratory responses to
HeO2 may involve "a reflex
effect" (15). Ward et al. (35) have suggested that changing from Air
to HeO2 may activate irritant or
other airway receptors, and this might contribute to the
I response to
HeO2 breathing.
Airway anesthesia and the ventilatory response to
HeO2.
The methods of Anesthesia used in this study were chosen to cause
anesthesia of the large airways where the effects of
HeO2 on turbulent airflow are
greatest (25). The method of aerosol anesthesia has been shown to cause
deposition of most of the anesthetic in the upper airways (oro-,
hypopharynx, larynx) and in the central intrathoracic airways (trachea,
hilum, large bronchi) (1, 28, 29). Aerosols of the particle size (5 µm) used in our study seldom deposit in the peripheral lung regions
or in the alveoli (1, 28). This method has been already shown to cause
large-airway anesthesia in previous studies in resting (10, 22) or
exercising (18) humans. Additionally, the method of topical laryngeal
anesthesia administration used in this study has been shown to block
afferents in the superior laryngeal nerve (21). The technique of
laryngeal anesthesia differed somewhat between this study and that of
Kuna et al. (21). Pledgets soaked in 4% lidocaine were held in each piriform recess for 1 min in our study and for 2 min in their study.
Also, 10% cocaine was dropped onto the epiglottis and vocal cords in
their study. Could the persistence of the
HeO2-induced sustained
hyperventilation with Anesthesia in our study be due to the shorter
duration of lidocaine application or the fact that cocaine was not
used? While this possibility cannot be completely excluded, we feel
that it is unlikely because we demonstrated the presence of Anesthesia.
Anesthesia of the upper and lower (central) airways was shown to be
present for over 15 min, as evidenced by the loss of gag reflex and the
cough response to inhaled citric acid, respectively, in all our
subjects. It has been shown previously that this method of Anesthesia
administration results in persistence of airway anesthesia during and
after exercise (18).
Anesthesia caused attenuation of the transient
I response to
HeO2 but did not affect the
steady-state I
response. The attenuation of the transient
I response
supports the notion that the respiratory adaptations to
HeO2 are related to its airway effects. It also supports the hypothesis that airway reflexes are
involved (15, 35).
While this study indicates that airway receptors are involved in the
immediate I
response to HeO2, it provides no
information as to which receptors may be involved. There are a large
number of receptors in the pharynx, larynx, and tracheobronchial tree, the activation of which could be altered by
HeO2. For example, the activation
of tracheal and bronchial irritant receptors, which respond to flow,
might be altered by HeO2 (31).
Because of their dynamic properties, tracheobronchial stretch-receptor
activation is influenced by flow rate (32). The larynx has a rich
supply of submucosal and mucosal receptors, some of which are sensitive to pressure and flow (33). Activation of these receptors may have been
altered by HeO2 breathing. Jammes
et al. (16) noted greater activation of laryngeal receptors by
HeO2 than by air, but this
occurred at 18°C, which is lower than the normal laryngeal temperature. Because of its noninvasive nature, the present study provides no information as to which of these receptors were activated (or inhibited) by HeO2.
Although the transient
I response to
HeO2 was attenuated by Anesthesia,
the steady-state response was unaffected. The reasons for this are
unclear. This suggests that, although the initial I response to
HeO2 is at least partly dependent
on airway receptors, activation of these receptors is not necessary for
the sustained response. It has recently been shown that increasing
inspiratory flow rate in mechanically ventilated subjects causes a
tachypneic hyperventilation, which is not sensitive to airway
anesthesia (13). It is possible that the initial
HeO2-induced increase in
inspiratory flow rate activates mechanisms not sensitive to Anesthesia,
which cause the sustained tachypneic hyperventilation and override the
resulting hypocapnia. It should be noted that the
HeO2-induced transient increase in
I in our
subjects was attenuated, not abolished, by Anesthesia; it is possible
that the attenuated initial increase in flow rate was enough to trigger the sustained hyperventilation. This hypothesis is speculative but
merits further study.
Is it conceivable that the effect of Anesthesia on the transient but
not the sustained hyperventilatory response to
HeO2 was due to a time-dependent
reduction in the intensity of Anesthesia during exercise? However, the
chances of that having occurred in this study are remote because there
was evidence of residual Anesthesia at end exercise in these subjects.
These results are similar to those from an earlier study
(18), in which the subjects had evidence of significant
Anesthesia after exercise. Furthermore, it was ascertained on an
initial occasion that each subject in this study had evidence of airway
anesthesia for at least the duration of exercise (i.e., 15 min).
HeO2 increases the maximum
expiratory flow-volume curve (24). Therefore, for the same
I and
breathing pattern, HeO2 reduces flow limitation when it is present during Air breathing. We did not
assess the presence of flow limitation in the present study. It is
possible that the
I response to
HeO2 may be related to its effect
of reducing expiratory flow limitation (6). This is supported by the
observation that the
I response to
inhaled CO2 during heavy exercise
falls, at levels of
I where
expiratory flow limitation develops (4).
Ventilatory control during HeO2
breathing may be further influenced by its effects on gas exchange.
Some (3, 37), but not all (26), studies have found that a decrease in
carrier gas density increases the alveolar-arterial
PO2 gradient. This, in itself, would
cause a small fall in arterial PO2 if
nothing else changed. However, this could not have contributed to the
HeO2-induced increase in
I in this
study because there was a small but significant increase in
SaO2 with
HeO2 breathing (Table 2).
Equipment resistance and helium hyperventilation.
HeO2 reduces external tubing
resistance, as well as internal airway resistance. To our knowledge,
previous studies of helium breathing during exercise did not match
equipment resistance for Air and
HeO2, although DeWeese et al. (8)
matched external resistance in their studies with
HeO2 at rest. Forster et al. (11)
noted a 47% fall in external resistance with
HeO2 breathing, compared with room
air breathing. This fall was almost the same as the fall in pulmonary
resistance in their studies. Increasing the resistive load at the mouth
causes a reduction in
I during exercise with room air breathing (9). It was therefore possible that
the HeO2-induced hyperventilation
is related to the reduction in external resistive load, not the change
in internal load. Therefore, we matched the external tubing resistance
during HeO2 to that during room
air breathing (Table 1). Despite this,
HeO2 caused significant
hyperventilation. Therefore, the hyperventilation with
HeO2 is not simply due to a change
in tubing resistance, although this may have accentuated the
hyperventilation in previous studies.
In conclusion, this study indicates that the transient, but not the
sustained, hyperventilation with
HeO2 is dependent on airway
afferents sensitive to topical anesthesia. The hyperventilation with
HeO2 breathing is not simply due
to a change in external equipment resistance.
ACKNOWLEDGEMENTS
This study was supported by an operating grant from the Medical Research Council of Canada. B. S. Krishnan and M. J. Stockwell were supported by research fellowships from the Canadian Thoracic Society, and C. G. Gallagher was supported by a scholarship from the Saskatchewan Lung Association.
FOOTNOTES
Address for reprint requests: C. G. Gallagher, Dept. of Respiratory Medicine, St. Vincent's Hospital, Elm Park, Dublin 4, Ireland.
Received 21 August 1996; accepted in final form 14 March 1997.
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