Vol. 89, Issue 6, 2258-2262, December 2000
Tracheal constrictor drive above the apneic threshold in
anesthetized dogs
J. A.
Silverman1,
L. Z.
Sommer1,
A.
Robicsek1,
J.
Dickstein1,
A.
Greenberg1,
J.
Kruger1,
J.
Rucker1,
G.
Volgyesi1,
J. A.
Fisher1, and
S.
Iscoe2
1 Department of Anaesthesia, Mount Sinai Hospital,
University of Toronto, Toronto, M5G 1X5; and 2 Department of
Physiology, Queen's University, Kingston, Ontario, Canada K7L 3N6
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ABSTRACT |
We have previously shown that raising arterial
PCO2 (PaCO2) by small
increments in dogs ventilated below the apneic threshold (AT) results
in almost complete tracheal constriction before the return of phrenic
activity (Dickstein JA, Greenberg A, Kruger J, Robicsek A, Silverman J,
Sommer L, Sommer D, Volgyesi G, Iscoe S, and Fisher JA. J
Appl Physiol 81: 1844-1849, 1996). We hypothesized that, if
increasing chemical drive above the AT mediates increasing constrictor
drive to tracheal smooth muscle, then pulmonary slowly adapting
receptor input should elicit more tracheal dilation below the AT than
above. In six methohexital sodium-anesthetized, paralyzed, and
ventilated dogs, we measured changes in tracheal diameter in response
to step increases in tidal volume (VT) or respiratory frequency (f) below and above the AT at constant PaCO2
(~40 and 67 Torr, respectively). Increases in VT
(400-1,200 ml) caused significantly more (P = 0.005) tracheal dilation below than above AT (7.0 ± 2.2 vs.
2.8 ± 1.0 mm, respectively). In contrast, increases in f
(14-22 breaths/min) caused similar (P = 0.93)
tracheal dilations below and above (1.0 ± 1.3 and 1.0 ± 0.8 mm, respectively) AT. The greater effectiveness of dilator stimuli
below compared with above the AT is consistent with the hypothesis that
drive to tracheal smooth muscle increases even after attainment of
maximal constriction. Our results emphasize the importance of
controlling PCO2 with respect to the AT when
tracheal smooth muscle tone is experimentally altered.
slowly adapting receptors; apnea; airway smooth muscle tone; respiratory drive; tone; upper airway
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INTRODUCTION |
USING A NEW METHOD OF
MEASURING tracheal diameter (8), we previously
showed that increasing arterial PCO2
(PaCO2) causes progressive tracheal constriction in
dogs ventilated to neural apnea, with most constriction occurring
before the onset of phasic phrenic activity [i.e., the apneic
threshold (AT)] (7). Above the AT, there is little or no
additional tracheal constriction, despite continued increases in
PaCO2. This may be because constrictor drive to
tracheal smooth muscle reaches its maximum at the AT or because the
trachea reaches a structural limit imposed by the cartilage. (We define
"drive" as the sum of all constrictor inputs to tracheal smooth
muscle and "tone" as the net tendency of the trachea to contract
under all constrictor and dilatory influences.) Discriminating between
these two possibilities is necessary to assess the effectiveness of any
dilatory stimulus. Differences in the prevailing level of constrictor
drive, i.e., the PaCO2, could account for the reported
variability of the dilatory responses of the trachea to increases in
tidal volume (VT) and respiratory frequency (f) (5,
21, 23).
Figure 1 illustrates two possible
relations between PaCO2 and constrictor drive. If
constrictor drive reaches a maximum at the AT (line B), then
a given dilating stimulus should result in equal dilations both above
and just below the AT. However, if constrictor drive continues to
increase in response to PaCO2 (line A),
then, at maximal tracheal constriction, a given dilating stimulus
applied under isocapnic conditions should elicit less dilation when
applied above the AT compared with below the AT, because of the
opposing effect of constrictor drive above the AT. We tested this
hypothesis by applying reproducible dilatory stimuli, consisting of
step increases in either VT or f, both mediated by slowly
adapting receptors (SAR) (14, 21, 22, 24).
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Fig. 1.
Schematic of the hypothesized effects of increased
respiratory drive on tracheal tone. As arterial
PCO2 (PaCO2) increases,
tracheal diameter decreases (see Fig. 3 in Ref. 7), with
most constriction occurring below the apneic threshold (AT; dotted
line). Below AT, constrictor drive increases as PaCO2
increases. Above AT, constrictor drive may continue to increase
(line A) or reach a plateau (line B).
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METHODS |
The study was approved by the Animal Care Committee of the
University of Toronto. Experiments were performed on six mongrel dogs
of either sex (weight = 20-25 kg). The dogs were initially anesthetized with 5-7.5 mg/kg body wt methohexital sodium and maintained with an intravenous infusion of 0.25-0.30
mg · kg
1 · min1. The
trachea was intubated with a 6.0-mm-ID endotracheal tube with a
modified cuff (8) for measurements of tracheal diameter. Adequacy of anesthetic depth was confirmed from the strength of the
corneal reflex, lack of spontaneous movements, and stable heart rate,
blood pressure, and f. During paralysis (see Protocol), we
used the same infusion rate but supplemented anesthesia (methohexital sodium, 30-60 mg as a bolus infusion) when heart rate or blood pressure rose.
The C5 root of the left phrenic nerve was exposed and cut distally. The
proximal end was desheathed and placed on a bipolar, silver hook
electrode. The activity of this nerve was amplified and
"integrated" using a resistance-capacitance circuit with a time
constant of 100 ms. A catheter was placed in the femoral artery to
allow for continuous measurement of blood pressure and periodic
sampling for blood-gas and pH analysis (ABL3, Radiometer, Copenhagen,
Denmark). Temperature was monitored using a rectal thermometer (43TD,
Yellow Springs Instruments, Yellow Springs, OH). Inspiratory and
expiratory CO2 concentrations were monitored continuously
(Ametek, Thermox Instruments, Pittsburgh, PA) from gas sampled at the
proximal end of the endotracheal tube. Airflow was measured with a
pneumotachograph (Vertek series 47303A, Hewlett-Packard, Palo Alto,
CA), and the signal was integrated to obtain volume. All analog signals
were digitized at 17 samples per second per channel (Dataq Instruments,
Akron, OH) and recorded using data acquisition software (AT-CODAS).
Phrenic activity was integrated off-line over 30-s intervals to provide
minute phrenic activity expressed in arbitrary units.
Protocol.
Dogs were initially ventilated with a conventional mechanical
ventilator at a VT of 400-450 ml and a f of 10-12
breaths/min. Inspired air was enriched with CO2 to control
the fractional concentration of inspired CO2
(FICO2). The
FICO2 was progressively lowered until phrenic nerve activity ceased; the value of PaCO2 or
end-tidal PCO2
(PETCO2) at which activity ceased was
termed the AT.
At this PaCO2, referred to as below AT, f was held
constant while VT was increased from control to 600, 900, and 1,200 ml and then returned to control. Next, at a constant
VT, f was increased from control to 14, 18, and 22 breaths/min and again returned to control. Each increment of f or
VT lasted 5 min, and an arterial blood-gas sample was drawn
at the end of each step. Changes in PaCO2 caused by
changes in ventilator settings were minimized using a circuit that
passively matched inspired CO2 to minute ventilation
(20).
To block spontaneous breathing movements above the AT, dogs were
paralyzed with 3 mg doxacurium chloride (Glaxo Wellcome, Missisauga,
ON, Canada), a long-lasting, nondepolarizing, highly selective
nicotinic receptor blocker with no autonomic side effects at the doses
used in this study. PaCO2 was then raised ~25 Torr above the AT by increasing FICO2 while
keeping ventilator settings at control values. At this new steady-state
level of PaCO2, referred to as above AT,
VT and f were increased using the same protocol as
described above while PaCO2 was
maintained at its new level using the same circuit as above.
All results are expressed as means ± SD. Comparisons of data were
made using appropriate tests, as described. Differences were considered
significant at P < 0.05.
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RESULTS |
Tracings from the protocol in which VT was increased
below and above the AT are shown in Fig.
2 (for dog 4).
Below AT, as VT increased from 400 to 1,200 ml, at
constant
PETCO2 (~42
Torr), tracheal diameter increased from 13.7 to 22.4 mm; above
AT, the same changes in VT at constant
PETCO2 (~75
Torr) dilated the trachea by only 3.8 mm, from 10.9 to 14.7 mm. Mean
changes in tracheal diameter and PaCO2 for all dogs in
response to increases in VT and f below and above AT are
provided in Table 1; increases in VT, especially below AT, dilated the trachea more
effectively than changes in f. Changes in neither f nor VT
affected mean arterial pressure (repeated-measures ANOVA).
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Fig. 2.
Tracings from dog 4 ventilated below
(left) and above (right) AT. As tidal volume was
increased in steps, tracheal diameter increased, and end-tidal
CO2 remained constant (~42 and 75 Torr, respectively).
au, Arbitrary units.
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Table 1.
Effect of changes in tidal volume and frequency on tracheal
diameter and arterial PCO2 below and above
the apneic threshold
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The effects on tracheal diameter of the maximal increases in
VT (from 400 to 1,200 ml) and f (from 10 to 22 breaths/min) below and above AT in all dogs are shown in Fig.
3. At VT = 400 ml, there was
no significant difference (P = 0.28, paired
t-test) in tracheal diameters below and above the AT;
however, in five of the six dogs, tracheal diameter was the same or
smaller above AT, consistent with our previous observations
(7). In response to increases in VT,
significant tracheal dilation occurred both below and above AT, with
the maximal increases being significantly greater (P = 0.005, paired t-test) below than above (7.0 ± 2.2 vs.
2.8 ± 1.0 mm, respectively) AT. When expressed as a percentage of
the tracheal diameter at VT = 400 ml, the average dilation caused by an increase in VT to 1,200 ml was 50% (range
25-63%) below AT but only 24% (range 15-37%) above AT. In
contrast, changes in f from 10 to 22 breaths/min did not cause more
tracheal dilation below than above AT (P = 0.93, paired
t-test). The only significant difference in mean tracheal
diameters below and above AT occurred at f = 10 breaths/min
(P = 0.046, paired t-test).
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Fig. 3.
Average changes in tracheal diameter for all dogs for
maximal changes in tidal volume (from 400 to 1,200 ml) or frequency
(from 10 to 22 breaths/min). * Significantly different from control
(P < 0.05); + significantly different from change
below AT (P < 0.05).
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Below AT, changes in VT did not affect
PaCO2 , but,
above AT, PaCO2 fell at VT = 1,200 ml
compared with values at VT = 400 and 600 ml (one-way ANOVA
for repeated measures and post hoc Student-Newman-Keuls test); however,
this drop did not exceed 3.6 Torr, despite a tripling of minute
ventilation. Changes in f did not significantly affect PaCO2 below or above AT. Below AT,
PaCO2 averaged 38.8 ± 5.4 Torr when VT changed, and 40.2 ± 6.2 Torr when f changed
(P = 0.416); above AT,
PaCO2 averaged
64.4 ± 6.9 Torr when VT changed VT and 67.3 ± 8.3 Torr when f changed (P = 0.156, paired
t-test).
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DISCUSSION |
Our results generate two main conclusions. First, under our
experimental conditions, identical increases in VT caused
greater dilation below than above AT, a result consistent with our
hypothesis that constrictor drive continues to increase above AT.
Second, at constant chemical drive
(PaCO2), larger tracheal
dilations resulted from increases in VT than from
increases in f, both below and above AT.
Measurement of tracheal diameter.
Pressure within an isovolumetric endotracheal balloon or the cuff of an
endotracheal tube has traditionally been used as an index of tracheal
tone. This method cannot, however, be used to measure constrictor drive
beyond the point of maximal constriction, because one cannot
distinguish between a plateau in drive and a physical limitation to
constriction. In addition, it is impossible to account for the unknown
limiting effects of muscle response and cartilaginous resilience in the
near-maximally constricted trachea. Nor can it be used to investigate
dilatory stimuli quantitatively, because once pressure is removed by
the initial tracheal dilation, no further readings are possible. In
contrast, isobaric changes in volume in a flexible endotracheal tube
cuff provide a sensitive, continuous quantitative measure of changes in
tracheal diameter in dogs over its full range of dilation (7,
8).
Effects of increased VT below and above AT on tracheal
diameter.
More tracheal dilation occurred below than above AT, a result similar
to the greater tracheal dilation caused by increased ventilation at low
compared with high CO2 levels observed by Stein and
Widdicombe (23). However, in the dogs of that study,
control tracheal diameters probably differed at the two CO2
levels. This is an important consideration because Stein and Widdicombe
(23) established that constricted airways are more
susceptible to volume-induced dilation.
The greater effectiveness of the dilatory influence of a given increase
in VT below vs. above AT may be due to factors other than
just increased drive. These include 1) differences in
susceptibility of the trachea to dilatory inputs below and above AT;
2) failure of increases in VT above the AT to
elicit the same increase in SAR feedback; 3) diminished
mechanical responsiveness of the trachea, possibly due to direct
effects of CO2 (e.g., Refs. 4 and 6); 4) differences in intrinsic properties (stiffness due to
actomyosin interactions) of the smooth muscle below and above AT
(10); and 5) diminished effectiveness of
dilatory inputs above the AT due to "central" processing.
We consider the first four explanations unlikely for the following
reasons. First, in the four dogs whose control tracheal diameters were
smaller above AT, a VT of 1,200 ml caused less tracheal
dilation above AT, even though these tracheae had a greater dilatory
reserve. Second, there should have been more, not less, SAR input above
AT because increased chemical (hypercapnic or hypoxic) drive increases
constrictor tone, which, in turn, augments SAR activity
(9). Although increases in CO2 inhibit SAR
discharge, this effect is negligible at the normo- and hypercapnic
levels (2, 4) used in our study. Third, although
CO2 induces dilation of airway smooth muscle (see Refs.
6, 13, and 16), the VT-induced dilation above AT (mean
PaCO2 = ~67
Torr) was still less than that below AT (mean
PaCO2 = ~40 Torr). The responses cannot be
attributed to a direct effect of either stretch or CO2 on
tracheal smooth muscle (see Ref. 19 and references to
previous work), because the endotracheal tube prevented exposure of the luminal surface to CO2 and because our isobarometric cuff
did not exert pressure on the trachea. Finally, Fredberg and colleagues (10) have proposed that cyclic stretching (i.e.,
VT) creates a dynamic equilibrium in terms of actomyosin
interactions, thus predisposing airway smooth muscle to lengthening
(or, for our purposes, tracheal dilation). According to their proposal,
already-dilated airways should, within structural limits, be even more
susceptible to dilatory stimuli. While we cannot exclude the effect of
differences in the stiffness of the smooth muscle on the ability of the
trachea to dilate, two dogs still dilated their tracheae more below AT, even though one started with a trachea of the same diameter both below
and above AT and the other started with a much larger diameter trachea
above AT.
We believe that the most reasonable explanation for the smaller
dilatory effect of VT at high CO2 (above AT),
other than the necessity to offset a higher level of constrictor drive
above AT, is that CO2 blocks the reflex effects of SAR
activation. Stein and Widdicombe (23) expressed the same
idea: "elevated chemoreceptor discharge reduces [the trachea's]
reflex response to mechanoreceptor discharge." We favor an
interaction between hypercapnia and SAR inputs at the parasympathetic
preganglionic neurons because hypercapnia-induced bronchoconstriction
persists after carotid body denervation (15), indicating
that central chemoreceptors are responsible. The proximity of central
chemoreceptors and parasympathetic preganglionic neurons (see Ref.
7 for discussion) would favor such an interaction. This
postulated interaction requires that parasympathetic preganglionic neurons should, at increased PaCO2, respond less to
SAR inputs; however, their responses to CO2 have not been investigated.
Effects of VT vs. f on tracheal diameter.
The reported effects of increases in VT and f on tracheal
dilation vary between studies. At constant respiratory drive in anesthetized dogs, increases in f but not VT cause tracheal
dilation (23), results that are very different from ours.
In contrast, our results are consistent with those of Sorkness and
Vidruk (21), who found that increases in VT
were marginally more effective than increases in f in dilating the
tracheae of awake dogs at constant PETCO2.
In addition, increases in the frequency of oscillations of tracheal
pressure over the same range as those used in our dogs decrease cuff
pressure (5), a result that is consistent with our own.
The reasons for these discrepancies (and agreements) are unclear and
may simply result from the unspecified and, likely, inconsistent
baseline (i.e., PaCO2) conditions and the
limitations of measurements with an isovolumetric cuff.
The greater tracheal dilation in response to VT rather than
f is supported by several studies comparing the static and dynamic sensitivities of SAR (see Ref. 18 for review) over the
ranges of VT and f used. Both in vitro (3) and
in situ (1, 17) studies of canine SAR indicate that the
static (volume-related) component of SAR sensitivity is responsible for
~65-85% of the receptor's discharge. Moreover, although the
flows our dogs were subjected to (~8-24 l/min) are within the
range in which the dynamic properties of the receptors contribute to
their increased discharge, as described by Pack and colleagues
(17), differences in tracheal dilation observed below and
above AT cannot be attributed to different flows, because we used
identical flows. Assuming no change in pulmonary mechanics or
end-expiratory lung volumes, the only difference below and above AT was
the CO2-related constrictor drive. As indicated, CO2 does not inhibit SAR discharge over the range of
PaCO2 encountered in our study. These results, along
with those of Sorkness and Vidruk (21) and our own,
indicate that increases in VT are more effective than
increases in f in activating SAR and, therefore, in causing tracheal dilation.
Implications.
Our results are consistent with the idea of constrictor drive
increasing even after maximal tracheal constriction is attained and
indicate that volume-related SAR feedback is more effective than
frequency-related SAR feedback in eliciting tracheal dilation. Our
results also emphasize the importance of knowing or controlling PaCO2 when experimentally assessing the effects of
dilatory stimuli. Few, if any, previous studies specify
PCO2 in relation to AT or control for changes
in PCO2 during interventions. Clinically, in
severe attacks of bronchospasm progressing to ventilatory failure, a
rise in PCO2 may also increase constrictor
drive and possibly antagonize the patient's response to
bronchodilators, thus resulting in further ventilatory deterioration.
If this does in fact occur in a clinical situation, intervention with
anticholinergic medication or sedatives may be less hazardous than the
risk of barotrauma due to mechanical ventilation. This mechanism may
also account for variations in the effectiveness of bronchodilators not
only between, but also within, subjects (11, 12).
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ACKNOWLEDGEMENTS |
This work was supported by the Ontario Thoracic Society.
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FOOTNOTES |
Address for reprint requests and other correspondence: S. Iscoe, Dept. of Physiology, Queen's Univ., Kingston, ON, Canada K7L
3N6 (E-mail: iscoes{at}post.queensu.ca).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 26 May 2000; accepted in final form 20 July 2000.
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ABSTRACT
INTRODUCTION
