435
clinical Science (1984) 66,435-442
The effects of oral almitrine on pattern of breathing and gas
exchange in patients with chronic obstructive pulmonary
disease
J . R . STRADLING, C. G. NICHOLL, D. COVER, E. E. DAVIES,
J . M . B. HUGHES A N D N. B. PRIDE
Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London
(Received 20 December 1982121 September 1983; accepted I1 October 1983)
summary
1. Almitrine at a low dose of 100mg orally
significantly raises Pao2 and lowers Paco2 in
patients with chronic obstructive pulmonary
disease, compared with placebo, when they were
breathing air or 28%oxygen.
2. The estimated ideal alveolar - arterial Po2
difference was less after almitrine compared with
placebo, when patients were breathing either air
or 28%oxygen.
3. After almitrine overall ventilation breathing
air increased by 10%but this did not reach statistical significance. During 28% oxygen breathing
almitrine hardly altered overall ventilation but the
inspiratory duty cycle (Ti/TtOt.) decreased and
mean inspiratory flow rate (V,/Ti) increased
compared with placebo. These changes were
significant on a paired t-test (P< 0.05).
4. Changes in both volume and pattern of
breathing may explain the improved gas exchange
in the lung after almitrine.
Key words: almitrine, control of respiration,
induction plethysmography, pulmonary gas exchange, respiratory failure, ventilatory stimulant.
Abbreviations: AaDo2, estimated ideal alveolar arterial difference for oxygen; COPD, chronic
obstructive pulmonary disease.
Introduction
Almitrine increases ventilation in animals and man
probably via an action on the peripheral chemoCorrespondence: Dr J. R. Stradling, Chest
Clinic, Churchill Hospital, Headington, Oxford,
U.K.
receptors. Thus it increases the response to
hypoxia in normal man but hardly affects the
hypercapnic drive [l]. Almitrine has been given
extensively to patients with chronic obstructive
pulmonary disease (COPD) at several centres
[2, 31. The results have usually shown small,
sometimes insignificant, increases in ventilation
(depending on dose) but large rises in Pao2 in
excess of the fall in Pace, [4]. The consequent
reduction in ideal alveolar -arterial difference for
oxygen (AaDo2) has not yet been explained. Both
Tenaillon et al. [S], who studied patients receiving
artificial ventilation, and Castaing et al. [6], who
used inert gas elimination techniques, have
suggested e a t improvements in ventilationlperfusion (VA/Q)matching in the lung are the cause.
Potentiation of local hypoxic vasoconstriction has
been postulated as a possible mechanism [4].
Animal studies have not in general supported this
hypothesis [7-lo].
The aim of this study was to examine the
effects of a low dose of almitrine, compared with
placebo, on ventilation with its subdivisions and
on gas exchange, during a steady state, in patients
with chronic obstructive pulmonary disease
breathing air and 28% oxygen. The reasons for
using oxygen breathing were twofold. First,
oxygen breathing limits the ventilatory response
to almitrine by lowering the level of activity in the
carqtid-body [ll], thus allowing any improvement
in V,/Q distribution to be revealed in the absence
of large changes in ventilation. Second, for the
same VA/Q maldistribution the AaDo2 is greater
with moderate increases in inspired oxygen
tension, which makes it more sensitive as an index
of VA/Qdistribution.
J. R. Stradling et al.
436
In this way we hoped to establish whether
favourable changes in Pao2 and AaDo2 could still
occur after almitrine in the absence of any changes
in ventilation.
Methods
Patients
Six patients with COPD (three males and three
females), who did not have a current exacerbation
of their disease, were given either almitrine (100
mg orally) or placebo (single blind and randomized)
on 2 separate days separated by more than 48 h.
Table 1 shows their basic physiological data. The
patients studied were heterogeneous, representing
a spectrum of patients with stable COPD. Before
the study all subjects took their usual medication.
Approval was obtained from the Research Ethics
Committee, Hammersmith Hospital, and subjects
gave their informed consent.
Techniques
Ventilation and its subdivisions &, VT,Ti/Ttot.
and VT/Ti) were measured without a mouthpiece
by using respiratory inductance plethysmography
(RIP, Respitrace) consisting of ribcage (RC) and
abdominal (AB) coils which were taped in position
to prevent slipping. The calibration of this system
was performed in two stages. First, a multiple
linear regression technique [ 121 was used t o obtain
the volume motion coefficients for RC and AB.
The digitized electrical output from a spirometer
(SP) was compared every 1 0 0 m s with digitized
signals from the RC and AB coils over a 2 0 s
period of ordinary breathing. The 200 sets of data
are assumed to be related, as originally suggested
by Konno & Mead [ 131, by the equation [ 141
SP = (ax RC)
+ ( b x AB)+ E
where a = the volume motion coefficient for the
ribcage movement (RC), b = the volume motion
coefficient for abdominal movement (AB) and
E = any voltage offset. Extraction of these volume
motion coefficients by this multiple regression
technique requires the RC and AB components
of ventilation to be a little out of phase or of
different shape; this has usually been the case in
our experience in patients with COPD. The data
collection and processing of the 200 simultaneous
equations was carried out by an Apple I1 microcomputer. The statistical consistency of the 200
comparisons was calculated by regressing SP (b x AB) against RC and SP - (a x RC) against
AB. If 95% of the individual readings were within
15% of the values predicted by the regression
lines for both ribcage and abdomen the calibration was considered satisfactory. Second, the
overall accuracy of this calibration in predicting
true V, was checked, with the subject breathing
from the spirometer again for at least 10 (mean =
28) normal breaths. The VT derived from the calibrated RIP system was compared with that from
the spirometer. The tidal volumes from the RIP
and the spirometer were detected separately to
allow for any phase shift between body surface
movements and volume changes at the mouth. The
mean difference over these test breaths was then
used to adjust the VT values subsequently
measured by RIP. The standard deviation of the
comparison could also be calculated to assess the
consistency of V, measurements and hence the
breath to breath accuracy of RIP.
After 41 satisfactory calibrations the mean of
the checks against the spirometer (spirometer
VT/RIP VT) was 0.98 with a SD of 0.10. The
average SD obtained in the 41 checks was 0.10 and
the SEM was 0.02, indicating that after calibration
and adjustment 95% of individual VT measurements were measured with an accuracy of 20%
but the 95% confidence limits for measurements
of mean VT were +4%. To assess the stability of
the calibration 12 comparisons with the spirometer were performed before and after a 2 h
period. There was no change in the spirometer
TABLE1. Basic physiological data for the six patients studied
FEVleo, Forced expiratory volume in 1.O s; VC, slow expiratory vital capacity.
Age
Subject
no.
(years)
1
2
3
4
5
6
63
61
68
62
61
56
Sex
F
M
F
M
M
F
FEV1.0
FEV1.01
PaCO,
AaDO
Oitre)
vc (%)
(mmHg)
(mmHg)
(mmHg)
0.40
0.40
0.50
0.54
0.80
0.62
36
16
42
52.8
78.5
56.3
69.4
46.9
40.4
49.0
43.1
46.0
35.8
43.8
69.1
35
17
35
35
47
22
ia
21
48
Pa0
Almitrine and gas exchange
VT/RIP V, ratio (before, 1.00, SD 0.09; after,
1.00, SD 0.10). The patients remained in the same
semi-recumbent position (maintained by a foot
board) throughout the experiment. Breath by
breath analysis was performed with a seven breath
ranking system. This system records tidal volume
(and its derivatives) as the median value of the.
current breath and the three breaths before and
after it, which removes transient artifacts such as
sighing and coughing. Mean values of any of the
ventilatory measurements were computed automatically at specified intervals.
Arterial samples were taken in triplicate, each
drawn over 1 min, from a small cannula (no. 23
butterfly, Abbott Laboratories) inserted in the
radial artery at the beginning of the experiment.
The samples were analysed only if a steady state
was present before and during the sampling as
judged by no discernible change in Saoz (by ear
oximetry: Hewlett Packard 47201A), ptCcoz(by
transcutaneous probe on abraded skin [15]:
TCM 20, Radiometer, Copenhagen) and the
ventilatory measurements. The arterial samples
were analysed for Poz and Pco2 on an ABLI
(Radiometer, Copenhagen) and the ideal alveolar
arterial differences for oxygen (AaDoz) were
calculated by assuming a respiratory exchange
ratio of 0.8 [16].
437
Vickers Medical) supplied with 4 litres of air/min.
During the last 10 min three arterial samples were
drawn from the cannula. Ventilation and its subdivisions were averaged over the last 0.5 h. A
comparison between the RIP and the spirometer
was made at the beginning and end of each hour.
Placebo or alimitrine was then given with half a
glass of milk. One hour later the RIP was recalibrated and recordings were made for a further
1 h period. Arterial sampling and ventilation
measurements were made as before. Without the
subject’s knowledge the Ventimask was then
supplied with oxygen (equivalent to 28%inspired)
instead of air. Towards the end of this hour the
arterial sampling and ventilation measurements
were made as for the first and third hours. A
comparison between the RIP and spirometer was
made at the beginning of the third hour and at the
end of the experiment to check for any change in
calibration. Blood was taken for almitrine levels at
1 , 2 and 3 h after tablet ingestion.
Two days at least were allowed between the
two studies on each patient. The same Ventimask
and flow gauge were used on all occasions.
Statistical analysis
The statistical analysis compared the changes
observed in each individual on the placebo days
with the changes observed on the almitrine days.
Student’s paired t-tests were used for this [17].
The actual changes analysed were: (1) those
occurring between the control and the post-drug
periods and (2) those occurring between the
control and the post-drug with 28% oxygen
period. Thus the significance of any differences
seen on the almitrine day was assessed.
Protocol (Fig.1)
The subjects attended on each day of the
experiment at 07.30 hours, having fasted overnight. After placement of the radial cannula,
connection to the equipment and calibration of
the RIP, a 1 h control period was recorded with
the subject wearing a face mask (Ventimask,
100 mg alrnitrine
or placebo
Air
I
Atmitrine
-1 h
*
-
Blood
,
gases
-
+.))) - --- - -- --- l
Ventilation
Sao
ptccoz
h
28% oxygen
Alrnitrine
byel
+
W?
Almitrine
+
ley4
*3
I
Ventilation
Ventilation
Sao
ptccoz
S&Z
ptccoz
FIG. 1. Experimental design. A full explanation is given in the Methods section.
PtCco2,
Partial pressure by transcutaneous probe on abraded skin.
J. R. Stradling et al.
438
TABLE2. Measurements of gas exchange and ventilation in b o t h placebo and almitrine
experiments
Means (and SEM) are shown.
Almitrine
Placebo
Pa0 ,
(mmHg)
PaCO ,
(mmW
AaDO,
(mmW
Ventilation
(l
min-')
Frequency
(min-')
Tidal volume
(ml>
TiPtot.
vT/Ti
(1min-')
Before
After
28%0,
Before
After
28%0,
57.3
(5.8)
47.8
(4.6)
31.9
(4.5)
7.0
(1.0)
19.4
(1.6)
379
(66)
0.34
(0.01)
21.3
(3.4)
58.0
(5.6)
46.9
(4.2)
32.4
(3.9)
6.6
91.3
(10.5)
49.2
(5.2)
46.9
(9.5)
6.5
59.3
(5.1)
49.0
(4.9)
28.5
(4.0)
6.8
(0.7)
19.1
(1.4)
370
(47)
0.36
(0.01)
19.3
(2.5)
67.5
(5.6)
44.7
(3.6)
25.7
(3.3)
7.5
(0.9)
19.1
(1.2)
401
(57)
0.34
(0.01)
21.4
(2.4)
111.3
(9.4)
46.2
(3.7)
30.5
(7.3)
6.9
(1.0)
18.4
(1.1)
3 84
(59)
0.33
(0.01)
21.3
(2.6)
(0.8)
18.3
(1.5)
371
(54)
0.34
(0.01)
19.0
(2.1)
Results
Table 2 shows the effects of placebo and almitrine
on ventilation and gas exchange. Fig. 2 shows the
percentage changes from control values with the
statistical significance of almitrine versus placebo
differences. Pao, and Pacoz showed no change
after placebo and the expected rise in Pao, and
Paco, after oxygen was seen. Almitrine raised
Pao, and lowered Paco, relative to placebo. This
was so during both air and 28%oxygen breathing.
In addition, almitrine produced a fall in the
&Doz relative to placebo which was more pronounced during oxygen breathing. This was a
variable effect and did not achieve statistical
significance.
Compared with placebo, almitrine increased
ventilation. Overall inspired ventilation increased
10% but fell back to control values with 28%
oxygen. The rise in ventilation was caused almost
entirely by a rise in VT. The changes in overall
ventilation did not quite reach statistical significance (P = 0.08) but the subdivisions, Ti/Ttot.
and VT/Ti, were significantly altered even during
28% oxygen breathing. The pattern of inspiration
after almitrine was faster, deeper and shorter,
followed by a longer expiration since frequency
was unchanged. These were small but consistent
changes.
Blood levels of almitrine were 80 with a SEM of
29; 208 with a SEM of 68 and 272 with a SEM of
54 ng/ml at 1, 2 and 3 h after ingestion, respectively. No significant correlation between blood
(0.8)
19.0
(1.1)
359
(58)
0.35
(0.01)
18.4
(2.2)
levels of almitrine and ventilatory stimulation was
seen.
Discussion
Techniques
With respiratory inductance plethysmography
(RIP) the effects of extra dead space and mouthpieces, which could have masked subtle changes in
breathing patterns [18], were avoided. The great
advantage of RIP was that continuous and uninterrupted measurements of ventilation were
made over long (1-2 h) periods. Though RIP is
less accurate than direct measurements, the error
signal was repeatedly checked against a spirometer,
and the same posture used throughout. With these
safeguards the error in the measurement of mean
ventilation was calculated as k 4% (95% confidence
limits), although individual tidal volumes are
measured less accurately (see the Methods
section). This is similar to previous studies on RIP
[19]. A loose fitting face mask (Ventimask) was
worn throughout the experiment. In other experiments no consistent or maintained alterations in
breathing occurred due to the presence of this
mask.
Oxygen consumption (vo,) and carbon dioxide
production (Vco,) were not measured because of
the disruption, transient change in ventilation and
consequent inaccuracy that introducing a mouthpiece for only part of the experiment would have
produced. Subjects were studied fasting and there
Almitrine and gas exchange
8
100-
4
c
50-
n
/**
A
0-
10
439
gd
o:+-xx
b-----
-8-
-
n
3
n
c
5g
5
o-&+
-10
30
3
a
-
-6
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-
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EI"
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l5
-----8
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0
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-
-
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-10-
0-Ty=Jq
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;
-
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-a
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a
lo*-
---
0 -
-5
1;-
.
I
I
Before
--r---- - T
I
After
Q
-10
-
/Li*
-----p--*
I
I
I
I
0 2
Before
After
0,
is no reason to suspect changes in VCO,, VO, or
respiratory exchange ratio during the experiments. Almitrine does not change respiratory
exchange ratio [20].
Ventihtwn
The resting ventilation in the patients was lower
than is usually found in experiments using mouthpieces [2, 21-23]. This is similar to experience
reported with normal subjects [l]. At this lower
level of ventilation a small ventilatory stimulant
effect of almitrine would be easier to detect. In
this study the 10% rise in ventilation after
almitrine is similar to other studies when
allowance is made for the do? [2,6,21,22].
Fig. 3 plots ventilation (V,) against hcoZand
against arterial oxygen saturation (Sao,). Whilst
breathing 28% oxygen after almitrine, ventilation
is higher although Pacoz is lower (Fig. 3(a)),
Sao2 exceeding 96%in both instances. In Fig.3(b)
ventilation is again hlgher under approximately
isocapnic conditions although Sao2 has increased
compared with the control. These relationships
are the reverse of the normal where ventilation
increases as Pacoz rises or Sao, falls and indicate
clearly that almitrine has shifted the stimulusresponse curve to the left with both chemical
J. R. Stradling et al.
440
8
-
n
I
.B
E
5
o (47) Pam,
~
46
47
48
49
50
PaCO, (mmHg)
100
95
90
85
80
SaO, (%)
FIG. 3 . Mean minute ventilation plotted against ( a ) mean arterial PCO2 (breathing
28% oxygen) and ( b ) mean arterial saturation (breathing air) for six subjects receiving
placebo ( 0 ) or almitrine (a).
stimuli. Relief of hypoxaemia (Fig. 2) has reduced
the stimulatory effect of almitrine but does not
abolish it completely. In dogs, the dose-response
curve for almitrine was shifted to the right by
breathing 100% oxygen compared with air, but
ventilation was still increased despite this removal
of the hypoxic stimulus to the peripheral chemoreceptors [ I ll. Similarly, in cats, after section of
the carotoid sinus nerves, mean inspiration flow
rate (VT/T~)still increased after almitrine even
though overall ventilation did not [24]. Sinus
nerve section alone would leave aortic chemoreceptor activity but in this preparation there was
no ventilatory effect from severe hypoxia.
Hannhart et al. [2] showed an increase in ventilatory sensitivity to carbon dioxide in patients with
air flow obstruction and chronic hypercapnia. A
larger dose of almitrine was given (0.5-1 mg intravenously) than in this study but the changes in the
pattern of breathing, in particular an increase in
VT/T~and a decrease in inspiratory duty cycle
(Ti/Ttot.), were qualitatively similar. In man the
increase in V,/Ti has been shown to exceed the
increase in VT [4] and in a recent study on
patients with COPD using RIP almitrine (1 mg/kg)
also increased I/' almost entirely through VT and
vT/Ti [251.
Gas exchange
The rise in ventilation and tidal volume with
almitrine compared with placebo would be
expected to raise Pao, and lower Paco,. The 7.8%
fall in Paco, is presumably linked to the 10%rise
in ventilation. In the absence of a change in pA/Q
distribution within the lung, the rise in Pao, is
more than expected from the fall in Paco, since
the
fell. On the other hand, it is unlikely
that V A / ~distribution will remain unaltered
during increased ventilation, particularly if the
pattern of breathing is also altered.
Vandevenne et al. [26] studied 14 patients with
COPD, having trained them to breathe more deeply
and slowly. VT was greatly increased (100%) but
with a reduction in total ventilation and no change
in alveolar ventilation. Despite an increase in Vo2
(1 5%) the Pao, rose more than the Paco, fell, and
thus AaDo, decreased. Most of this extra V,
went to the lung bases. Although the changes in
VT were considerably more than those reported
in this paper the importance of the pattern of
breathing to gas exchange is clear. The two
patients in this study with the biggest increase in
V,/Ti after almitrine were also the two with the
biggest fall in AaDo,. To quantify changes in local
VJQ due to subtle changes in breathing pattern
in patients with COPD would be very difficult. An
alternative approach would be to mimic accurately
the changes in breathing pattern seen in this study
and examine any change in gas exchange.
Transient rises in pulmonary artery pressure
have been reported [27] after almitrine infusion.
This would redistribute blood flow away from
dependent parts of the lung [28] and might improve V'/Q matching. Aftef oral almitrine * a
favourable redistribution of Q in relation to V,
has been reported by Rigaud et al. [29], using
radioisotopes and external counting, principally
in normocapnic patients. As already mentioned,
Almitrine and gas exchange
potentiation of local hypoxic vasoconstriction
seems an unlikely mechanism [7,9,10].
Conclusions
An improvement in gas exchange after almitrine
has occurred with small changes in total ventilation and its subdivisions. Some of the improvement in blood gas tensions can be ascribed to the
increase in minute ventilation, but part of the
increase in Paoz (reflected in a decreased AaD0.J
may be due to more subtle changes in the pattern
of breathing, particularly speed and depth of
inspiration.
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