Occlusion Pressure Responses in Asthma and Chronic Obstructive Pulmonary Disease'-· H. ZACKON, 4 P. J. DESPAS, and N. R. ANTHONISEN
SUMMARY ___________________________________________ _______________ During C0 2 rebreathing we measured ventilation and the pressure generated during the first 0.1 sec of inspiratory effort against a closed airway (P 0 . 1 ) in 12 asthmatics during acute exacerbation, 10 nmmal subjects, and 10 patients with chronic obstructive pulmonary disease. In normal subjects, the ventilatory response to C0 2 correlated with the P 0 . 1 response measured as ~In P 0 . 1 . Patients with chronic obstructive pulmonary disease showed depressed responses to C0 2 in terms of both ventilation and ~In P 0 . 1 . However, P 0 . 1 values in the patients with chronic obstructive pulmonary disease were greater than those of the normal subjects when they were compared at an alveolar Pco 2 of 60 mm Hg. Asthmatics' responses to C0 2 were similar to those of patients with chronic obstructive pulmonary disease. When measured at an alveolar Pco 2 of 60 mm Hg, asthmatics' P 0 . 1 values were greater than those of both normal subjects and patients with chronic obstructive pulmonary disease. As the asthmatics' airway obstruction decreased so did their P 0 . 1 . The asthmatics, and to a lesser extent the patients with chronic obstructive pulmonary disease, demonstrated increased inspiratory muscle activity that could not be explained on the basis of chemical drive or alterations in functional residual capacity. In the case of the asthmatics it was possible that the increased inspiratory muscle activity was a 1·esponse to airway obstruction.
Introduction Since the observation that patients with chronic obstructive pulmonary disease (COPD) showed little increase in ventilation in response to inhaled C0 2 , the nature of ventilatory control in disease has been controversial. Lack of ventilatory response to C0 2 has been interpreted as loss of chemoceptor sensitivity (l). However, Brodovsky and co-workers (2) showed that ventila(Received in original form September 10, 1975 and in revised form August 6, 1976) 1 From the Respiratory Division, Royal Victoria Hospital, and the Montreal Chest Hospital Centre, McGill University, Montreal, Quebec, Canada. 2 Supported by the Medical Research Council of Canada and Quebec. 3 Requests for reprints should be addressed to Dr. N. R. Anthonisen, Respiratory Division, F-2 General Centre, Health Sciences Centre, 700 William Avenue, Winnipeg, Manitoba, Canada. 4 Fellow of the Quebec Medical Research Council.
tory responses were to some extent dependent on lung mechanics and that in disease a "normal"..-increase in respiratory muscle activity would provide a less than normal increase in ventilation. The issue was not how much the diseased patient breathed but how hard he or she was trying to breathe. Milic-Emili and Tyler (3), studying normal subjects breathing C0 2 with and without added external resistance, found that alveolar Pco 2 (P Aco 2) was uniquely related to inspiratory work rate and suggested that inspiratory work rate was a useful index of neural output to the respiratory muscles. Inspiratory work rate is difficult to measure, however, and there have been suggestions that during elastic loading inspiratory work rate was not uniquely related to PAco 2 (4). Recently, Whitelaw and associates (5) indicated that inspiratory muscle output may be quantitatively reflected by P O.l' the pressure developed at the mouth during the first 0.1 sec of inspiratory effort against an occluded airway. This measurement, because it is
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 114, 1976
917
918
ZACKON, DESPAS, AND ANTHONISEN
TABLE 1 1-SEC FORCED EXPIRATORY VOLUME (FEV 1 )/FORCED VITAL CAPACITY (FVC) FOR ASTHMATICS IN THE PRESENT STUDY AND THE BEST AND WORST VALUES FOR THE PRECEDING 3 YEARS
Subject
Age (years)
Sex
Car Aud Roy Tur Lon Sou Med Gos Hec Lap Cro Mih
68 35 27 39 80 44 68 48 53 43 64 45
M F F F F M M M F F M M
FEV 1 /FVC (/iter)
Predicted Normal Vital Capacity (/iter)
Present
3.8 3.4 3.1 3.6 2.5 4.8 4.0 3.9 3.8 3.1 3.5 4.5
static, shou!d not be influenced by the compliance or resistance of the respiratory system; it also should not be affected by volume-related vagal influences (5). Several groups (6-8) have shown that in normal subjects P 0 _1 was increased by added inspiratory resistance, indicating that acute increases in resistance may be ac-
Best
Worst
Study (First)
2.0/4.2 3.0/4.2 3.0/3.6 3.1/4.6 1.5/1.9 4.0/6.0 2.5/4.6 3.6/5.2 2.5/3.0 1.5/2.6 2.6/4.1 2.8/4.6
0.6/1.8 0.7/1.8 0.6/1.1 0.5/0.8 0.5/1.1 1.1/3.0 0.8/2.9 0.7/2.3 0.5/1.0 0.6/1.2 0.8/2.4 0.5/1.0
1.2/3.6 1.9/1.9 1.8/3.1 0. 7/2.4 1.0/1.6 1.8/3.5 0.8/3.3 2.1/3.4 1.7/2.3 1.0/1.9 1.3/3.2 1.8/3.9
companied by increased inspiratory muscle output. To determine if this finding has relevance in disease, we measured P 0 _1 in a group of asthmatics during exacerbations of their illness. Materials and Methods Twelve asthmatics were studied during hospitaliza-
TABLE 2 PULMONARY FUNCTION TEST VALUES AND PREDICTED NORMAL VALUES (IN PARENTHESES) IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (/iter)
vc
FRC (/iter)
1.6
2.8 (4.1)
5.0 (3.5)
4.0 (2.1)
44
26
M
1.1
2.5 (3.4)
4.5 (3.4)
3.5 (2.3)
39
24
54
M
1.1
2.9 (3.5)
5.0 (3.5)
3.6 (1.9)
38
24
Win
73
M
1.3
1.8 (3.7)
4.9 (3.8)
4.1 (2.5)
39
25
Dee
30
M
2.2
3.7 (5,2)
5.1 (4.0)
3.1 (2.0)
67
40
24
Tre
55
M
1.3
2.2 (3.5)
4.6 (3.1)
4.1 (1.9)
60
45
27
Niz
68
M
0.9
2.1 (3.1)
3.6 (3.0)
3.0 (2.0)
75
41
26
Mai
55
M
1.7
3.2 (3.1)
5.1 (3.2)
3.8 (2.2)
83
36
25
Rae
64
M
2.3
4.1 (3.7)
63
37
20
Mak
68
M
0.6
2.2 (3.3)
64
42
26
Subject
Age (years)
Sex
FEV 1 (/iter)
Gui
49
M
Cam
71
Lus
5.1 (3.3)
RV (/iter)
4.1 (2.2)
Hco;) Pao 2 Paco 2 (mm Hg) (mm Hg) (mEq/liter)
67
Definition of abbreviations: FEVr =forced expiratory volume in 1 sec; VC =vital capacity; FRC =functional residual capacity; RV = residual volume; Pao 2 = arterial 0 2 tension; Paco 2 = arterial C0 2 = tension; HC03 = bicarbonate.
919
OCCLUSION PRESSURE RESPONSES IN ASTHMA AND COPD
tion for acute exacerbations of their illness. All had been followed for at least 3 years with spirometric tests, and within that time all had demonstrated virtually normal function. Values of !-sec forced expiratory volume (FEV 1 ) measured at the time the patients were studied are compared in table l with the best and worst values that had been recorded during the preceding 3 years. None had chronic cough and sputum and all had experienced acute exacerbations in the absence of clinical evidence of respiratory infection. All were studied after recovery from the acute episode had begun. All were taking oral aminophylline preparations and inhaled B 2 stimulants, and most were taking oral corticosteroids. Ten normal men 26 to 36 years of age were also studied, 2 of whom had had previous experience as experimental subjects. Ten patients with COPD were also studied. These patients had been followed for more than a year, had chronic cough, sputum, and dyspnea, and were not subject to acute exacerbations of their symptoms in the absence of respiratory infections. None had C0 2 retention. All were regarded as stable by their physicians. This impression was supported by measurements of vital capacity and FEV 1 carried out on the day of the study; these results were the same as those of similar measurements made at least a month earlier. All of these patients were taking inhaled B 2 stimulants, and most were also taking aminophylline orally. Pulmonary function test values in these patients and predicted normal yalues (9) are shown in table 2. Lung volumes were determined by spirometrv and helium dilution, arterial blood gas values by appropriate electrodes. Subjects were studied in the seated position while rebreathing from a 6-liter bag containing 93 per cent 0 2 and 7 per cent C0 2 , as described by Read (10). The breathing circuit was modified so as to contain a breathing valve separating inspired and expired gas. Circuit resistance was 1.5 em H 2 0 per liter • sec and linear to 4 liter per sec. The expired line was sampled by an infrared C0 2 meter (Godart) at a rate of 1.0 liter per min, and this gas returned to the circuit. The inspiratory line contained a short length of compliant rubber tube in a plastic box. Mouth pressure was measured by a strain gauge (Sanborn 267B) connected to a needle that pierced the mouth· piece. The rebreathing bag was encased in a box and ventilation was measured by spirometrically recording box volume. Ventilation and mouth pressure were recorded on an oscillograph (Sanborn) at paper speeds of 50 mm per sec during occlusion. C0 2 concentrations were recorded as a function of time on another recorder (Beckman) with a 10-inch span. After familiarizing themselves with the equipment, subjects rebreathed from the circuit for at least 4 min. The inspired line was occluded during expiration at intervals of approximately 30 sec. The single occlusion never lasted longer than a single inspira-
tion and usually less. The subjects could neither see nor hear the occlusion, and the timing of the occlusions was varied enough so that subjects could not predict when occlusions would occur. During the same laboratory session both asthmatics and patients with COPD underwent duplicate measurements of FEV 1 , and in 5 of the asthmatics functional residual capacity (FRC) was also measured by plethysmography. One or more days after the initial experiment, studies were repeated in the asthmatics. In 9 of them the FEV 1 had increased by at least 0.3 liter over that measured at the time of the first study. In the other 3 patients the FEV 1 at the time of the second study was within 0.1 liter of that measured during the first study. Two normal subjects and 3 patients with COPD were also restudied in similar fashion. Ventilatory responses were analyzed by computing (least squares method) the slope of the response curve AVE/ APAco 2 , where VE is minute ventilation. The increase in P 0 _1 with PAco 2 was often not linear. To analyze our P 0 _1 -PAco 2 curves we followed the suggestion of Whitelaw and associates (5), who expressed these curves in the form InP 0 _1 =bPAco 2 +a. We computed b for each subject by the least squares method; increasing values by b therefore represented, in terms of P 0 _1 , increasing sensitivity to C0 2 . In our subjects, correlation coefficients between hJ
80
Des
0
•
Par
0
• 0
0.
•
0
•
P0.1 16 cm~O
12 8 4
0
0 0 0
•• •
•
•
0
60
80 80 PAc02 ,mmHg
80
Fig. l. Ventilatory and Po. 1 responses in 2 normal subjects (Des and Par) studied on 2 occasions. Upper panels show minute ventilation (VE) as a function of alveolar .Pco 2 (PAco 2 ); the lower panels show Po. 1 as a function of C0 2 • Open circles represent results of the first study, closed circles the results of the second.
920
ZACKON, DESPAS, AND ANTHONISEN
Njz
Tre
Mai
~ • 0
0
P0.1 c:mH2o
0 0
o. o.
0
•
•
0
50
•
~·
80
70
80
50
PAc02 ,mmHa Fig. 2. Ventilatory and Po. 1 responses in 3 subjects with chronic obstructive pulmonary disease studied on 2 occasions. Upper panels show minute ventilation (VE) as a function of alveolar Pco2 (PAco 2 ); the lower panels show Po.l as a function of PAco 2 • Open circles are results of the :first study, closed circles the results of the second. PO.l and PAco 2 were significantly better (P < 0.05 by paired t test) than those between P 0 . 1 and PAco2 . These analyses expressed responses to changes in PAco 2 . We also compared ventilatory and P 0 . 1 responses at a fixed level of C0 2 , PAco 2 of 60 mm Hg. This value was chosen because it was encom-
Mih
VE
eo
40
L/mi~
0
•
0i0.
0
i
•
Cro
Lap
o.o.
o o••
o•
passed by response curves in all subjects, so that ventilation and P 0 . 1 at PAco 2 of 60 mm Hg could be derived by interpolation rather than extrapolation. Results for each group of subjects were averaged, and when variances were equal, the means were compared by t test; this was seldom the case, however.
ia. • i
0
.o
.,
0
0
3 •
0
16
P0.1
0
oo
anH~ 0
0
0
0
•
12
4
• •
0
•o•
0.
•
••o eo
•
e•
•
0
oe
0
oe
0
oe
0
oed'
50
70
80
80
80
10
PAc02 ,mmHg Fig. 3. Ventilatory and Po. 1 responses in 3 asthmatics who were studied on 2 occasions when their 1-sec forced expiratory volume differed by .;;; 0.1 liter. Upper panels show ventilatory responses to alveolar Pco2 (PAco 2); lower panels show Po. 1 responses to PAco 2• Open circles are the results of the first study, closed circles the results of the second.
921
OCCLUSION PRESSURE RESPONSES IN ASTHMA AND COPD
TABLE 3 RESPONSE TO C0 2 REBREATHING IN NORMAL SUBJECTS Po.t t
VEt
Subject
(liter/min • mm Hg)
b*
(em H 2 0)
(/iter/min)
Nus Rah Par Sou Des Kar Bru Ott Hor Fri Mean SD
4.0 1.2 1.2 0.4 4.6 1.0 3.3 10.0 4.3 2.3 3.2 0.3
0.128 0.065 0.061 0.066 0.111 0.095 0.097 0.195 0.206 0.078 0.110 0.052
4.0 4.0 1.5 0.5 3.0 3.0 3.0 8.0 1.5 2.0 3.0 2.1
40 22 20 13 35 27 21 57 40 10 28.5 14.0
AVE/A PAco 2
alveolar C02 ten· Definition of abbreviations: \IE = minute ventilation; PAcoz sion; Po. 1 = pressure during the first 0.1 sec of inspiratory effort against an occluded airway. • From In P 0 • 1 = b PAco 2 +a. tAt PAco 2 of 60 mm Hg.
When variances were unequal, mean values were compared by the Wilcoxon-Mann·Whitney (WMW) test (11). Results Examples of ventilatory and P 0 _1 responses to C0 2, each done in duplicate, are shown in figures 1 to 3. Figure 1 shows results of 2 studies in normal subjects, figure 2 show~ similar results in 3 patients with COPD, and figure 3 shows results in the 3 asthmatics in whom the FEV1 changed by 0.1 liter or less. In all cases, results of first and second studies differed little. Responses in our normal subjects are summarized in table 3. Ventilatory responses (A"VE/ tiP Aco 2) averaged 3.2 liter per min· mm Hg, but varied widely in this group, ranging from 0.4 to 10.0 liter per min • mm Hg. Values forb varied less, their mean being 0.11 0. There was a correlation (r 0.81, P < 0.01) between t'lVE/ t'lPAco 2 and b (figure 4), indicating that subjects in whom C0 2 induced large changes of ventilation also showed relatively large changes of P 0 . 1 . At PAco 2 of 60 mm Hg, P 0 . 1 averaged 3.0 em H 2 0 and mean ventilation was 28.5 liter per min. Ventilatory responses of the patients with COPD are summarized in table 4. Values for t'lVEjtlPAco 2 were low, averaging 1.0 liter per min • mm Hg. This was significantly less (P < 0.05, WMW) than those found in the normal subjects. Values of b in the patients with COPD averaged 0.065, which was also significantly less (P < 0.05 WMW) than those of normal subjects. Among patients with COPD there was no corre-
lation between band LlVEjtlPAco 2 . At PAco 2 of 60 mm Hg, VE did not differ from that observed in normal subjects, but P 0 . 1 averaged 4.8 em H 2 0, higher (P < 0.05, WMW) than the value found in normal subjects. P 0 . 1 values at PAco 2 of 60 mm Hg are shown for normal subjects and patients with COPD in figure 5. Asthmatics' responses are summarized in table 5. The initial ventilatory responses to C0 2 were similar to those of tl1e patients witll COPD, averaging 1.3 liter per min • mm Hg. However, LlVE/ tlPAco2 tended to vary more in the asthmatics, b
• •
=
•
•
•
2
4 ~-
VE/6PAco2
Fig. 4. Correlation between ventilatory and Po. 1 re· spouses to C0 2 in normal subjects. Abscissa shows slope of ventilatory response to alveolar Pco 2 ( PAco 2 ); ordinate shows slope of the relationship of In Po. 1 to PAco2 (b = Llln Po. 1 /APAco2). Each point represents a normal subject.
922
ZACKON, DESPAS, AND ANTHONISEN
TABLE 4 RESPONSE TO C0 2 REBREATHING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE Po.t
.O.VE/.O.PAco 2
Subject
(/iter/min • mm Hg)
Gui Cam Lus Win Dee Tre Niz Mai Rae Mak Mean SD
0.5 1.2 1.2 0.3 0.6 1.6 0.8 0.8 2.1 0.9 1.0 0.5
b 0.024 0.105 0.062 0.041 0.034 0.092 0.066 0.082 0.072 0.074 0.065 0.026
.
VE •
(em H 2 0)
(/iter/min)
3.0 3.0 6.0 4.0 3.0 7.0 5.5 4.5 5.5 6.5 4.8 2.3
18 13 25 18 22 36 18 19 50 19 23.8 11.0
*At PAc02 of 60 mm Hg. For definition of abbreviations, see table 3.
and their mean !iVE(!iPAco2 did not differ from that of the normal subjects. Initial value for b was 0.061, similar to that of patients with COPD and less (P < 0.05 WMW) than that of the normal subjects. There was no correlation between values of !iVE(!iPAco2 and values of b. On their initial study the asthmatics showed large P 0 . 1 values at PAco 2 of 60 mm Hg (figure 5). The average value was 12.4 em H 2 0, significantly greater than that of normal subjects (P < 0.001, WMW) and of patients with COPD (P < 0.01, WMW). Ventilation at PAco2 of 60 mm Hg did not differ among the 3 groups. On repeat study, 9 of the asthmatics demonstrated an increase in FEV1 of at least 0.3 liter. In these patients !iVE(!iPAco2 changed in unpredictable fashion, as did b. However, P 0 . 1 at PAco 2 of 60 mm Hg decreased in all 9 subjects (table 5), whereas ventilation did not change consistently. Complete response curves in 3 of these patients are shown in figure 6. There was little change in P 0 . 1 at PAco 2 of 60 mm Hg in the 3 asthmatics who showed little change in FEV1 (table 5; figure 3). When first and second studies of all our asthmatics were considered, there was a significant correlation (r = 0.67; P < 0.02) between the per cent increase in FEV1 and the per cent decline in P 0 . 1 at PAco 2 of 60 mm Hg (figure 7). FRC was initially increased in the 5 patients in whom it was measured, and in 4 of them it had decreased at the time of the second study. Mean data from tables 3, 4, and 5 are represented graphically in figure 8; only the first study of the asthmatics is shown. Although figure 8 was constructed by combining mean values for
!iVE(!iPAco 2 and b with mean VE and l'0 . 1 at PAco 2 of 60 mm Hg, the resulting curves give accurate representations of mean VE and mean P 0 . 1 at PAco 2 of 55 mm Hg and 65 mm Hg. Ventilatory response was greatest in normal subjects, with results in asthma and COPD differing little (figure SA). P 0 . 1 responses are shown in 2 ways, on a loga.rithmic scale (figure SB) and an algebraic one (figure BC). It can be seen that In P 0 . 1 increased more rapidly in normal subjects as indicated by the relatively large values for b in table 3. However, in our asthmatics and patients with COPD, P 0 . 1 values at low PAco 2 were high. Therefore, although these patients had low values for b, their absolute increases in
p 0.1 PAco 2 =eo em H 2o
• •
•• •
.. I
•
L I
•• :.
-
N
COLD
•
•
•
•
ASTHMA
Fig. 5. Values for Po. 1 measured at alevolar Pco2 (PAco 2 ) of 60 mm Hg are shown for the first study of all subjects, grouped according to diagnosis. N normal; COLD "'chronic obstructive lung disease.
923
OCCLUSION PRESSURE RESPONSES IN ASTHMA AND COPD
TABLE 5 RESPONSE TO C0 2 REBREATHING IN PATIENTS WITH ASTHMA Subject
Study
FEV 1/FVC
FRC
(liter)
(liter)
VE/PAco 2 (liter/min • mm Hg)
6.0 5.4
1.2 1.4
Cor
2 2
1.2/3.6 1.5/4.2
Aud
2 2
0.9/1.9 1.7/2.9
Roy
2 2
Tur
2 22 2 22 2 212 21 22
1.8/3.5 2.2/3.7
Gas Hec
b
.
Po.t (em H 2 0)
VE* (/iter/min)
11.0 6.0
30 28
0.7 1.9
0.087 0.080 0 0.060
22.0 9.0
28 38
1.8/3.1 2.2/3.4
1.5 0.8
0.086 0.097
25.5 9.0
29 22
0.7/2.4 1.2/3.6
0 0.8
0.050 0.045
17.0 7.0
17 20
1.0/1.6 1.7/2.0
1.5 1.1
0.074 0.033
11.5 6.0
30 28
5.9 4.9
1.4 1.8
0.091 0.074
3.0 2.0
23 18
0.8/3.3 1.5/3.8
5.5 5.5
1.2 1.1
0.068 0.073
4.5 3.0
20 24
2 22
2.1/3.4 2.8/5.2
5.2 4.8
2.0 2.0
0.078 0.106
18.0 10.0
64 40
2 22 121 2121 212
0.7/2.3 1.4/3.2
5.2 3.9
0 1.0
0.057 0.050
16.0 7.0
22 22
1.011.9 1.1/1.8
0.8 0.7
0.033 0.024
7.0 8.0
14 16
22
1.3/3.2 1.3/3.2
1.4 1.4
0.044 0.047
22 21
Min
2 22
1.8/3.9 1.9/3.8
1.4 1.5
0.061 0.069
6.5 6.0 7.0 7.0
Mean
2 21 122
1.3/2.8 0.5 0.6
1.1 0.6
0.061 0.026
12.4 7.2
26.7 12.7
1.7/3.4 0.5,0.9
1.3 0.4
0.063 0.026
6.8 2.4
25.2 7.4
Lon Bou Med
Lap Cro
so
Mean
so
25 28
• At PAco 2 of 60 mm Hg. For definition of abbreviations, see tables 2 and 3.
P 0 . 1 with PAco 2 were comparable to those of nor mal subjects (figure 8C). Discussion
In comparing our 3 subject groups, it should be noted that there were obvious nonrespiratory differences among them. The normal group was younger than either the asthmatics or the patients with COPD. Furthermore, half the asthmatics were female, whereas all other subjects studied were male. It is possible that these differences influenced our results. We have measured P 0 _1 in a few young normal women, andresults were similar to those in men (6; Unpublished observations). In the present study female asthmatics did not differ from male asthmatics. \Ve do not believe that sex differences were responsible for our results. To our knowledge no measurement of P 0 . 1 in older normal subjects has been reported, but we are unaware of any a priori reason for supposing that values
of P 0 . 1 should increase with age, and we are inclined to discount this possibility. There was no significant difference between the mean age of our asthmatics and the mean age of our patients withCOPD. Our results in normal subjects were very similar to those of Whitelaw and associates (5), who examined a similar group of subjects with the same technique. However, previous workers (5, 6) have been unable to show inter-individual correlation between ventilatory and P 0 .1 responses to C0 2 • This failure was believed to be due to inter-individual differences in the relationship between VE and P 0 .1 . Comparing ventilatory and P 0 . 1 responses to C0 2 is equivalent to examining the relationship between VE and P o.I> and if this relationship varies substantially among individuals, correlations of ventilatory and P 0 . 1 responses to C0 2 will be poor. We found (figure 4) a significant inter-individual correlation between ventilatory and P 0 . 1 responsiveness.
924
ZACKON, DESPAS, AND ANTHONISE:-.1
Aud
Hec
Ve
•
Lfmin
0
0
•
i •
Roy
••
••
•o o
0
o
• •aao •
0
o•o • ooe
o~.----------r--
40 0
P0.1 em H20
32
0
0
24 16
0 0 0
•• 0
0
0 0
50
•
0
0
0
0
00
0
• ••
0
• • • •• •
70
••
0
••
..
•• •
•
50
70
50
0
0
PAc 02 ,mmHg
Fig. 6. Ventilatory and Po. 1 responses to C0 2 in 3 asthmatics who demonstrated less airway obstruction (increase of 1-sec forced expiratory volume of at least 0.3 liter) at the time of the second study (closed circles) than they did in the first (open circles). Upper panels are ventilatory responses to C0 2 ; lower panels are P0. 1 responses. This may have been because our normal group showed a greater range of values for both AVE/ ~PAco 2 and b than did groups examined in previous studies. The presence of extreme values probably helped in establishing a relationship. Our patients with COPD demonstrated low values of AVEjAPAco 2 , as expected (1). They also demonstrated low b. However, figure 8 illustrates that decreased values for b do not necessarily mean that the absolute increase in P 0 _1 was Jecrea,ed. Indeed, the absolute increase in P 0 _1 with C0 2 in our patients with COPD was only slightly diminished (figure 8C). This finding was in agreement with those of Maranetra and Pain (12), who, using a different occlusion technique, found no difference in change of occlusion pressure with PAco 2 between normal subjects and patients with COPD. It is clear that there are serious objections to considering the relatively low b found in patients with COPD as indicative of reduced P 0 _1 responses in these patients. The lack of correlation between b and ~ VE j APAco 2 was not surprising because the presence of such a correlation would have implied a similar relationship between VE and P 0 _1 among these patients. Lung mechanics varied among the patients and presumably affected VE more than P 0 _1 •
P 0 _1 values measured at PAco 2 of 60 mm Hg were greater in our COPD patients than in our normal subjects. FRC was increased in the COPD patients (table l ), and other things being equal, increases in FRC should decrease P 0 . 1 (5). We therefore concluded that at PAco 2 of 60 mm Hg our COPD patients demonstrated increased activity of the inspiratory muscles. The 6FEV1.0
-2o
o
20
,"fo
4o
60
ao
100
·2~---L--~--~--~--~~
6P0.1 -20 ..._co2·60 -40
"'o
..
-60 -10 -1
Fig. 7. Correlation between change in 1-sec forced expiratory volume (FEV d and change in Po. 1 in the asthmatics. Ordinate shows change in Po. 1 measured at alveolar Pco 2 (PAco 2 ) of 60 mm Hg, expressed as a percentage of the value noted during the initial study. Abscissa shows change in FEV 1 expressed as a percentage of the FEV 1 measured at the time of the first study. Each point represents an asthmatic patient.
925
OCCLUSIO)>.[ PRESSURE RESPO"'SES IN ASTHMA AND COPD
•
A
I
VE L/mW..
I
.I
p 0.1
, '
,
I
I
I
PO.l em H2 0
cm~O
/
I
c
. 'I
,•'/
..w'./
I
_,,j
I
/1
/
/
oL-~----r---~-
50
60
70
60
50
70
0
50
--··? -
-·
60
70
PAC02 mmHg
Fig. 8. Mean C0 2 response curves of the 3 groups studied; the asthmatics' second study is not shown. In panel A, ventilation is plotted against alveolar Pco 2 . In panel B, Po. 1 is plotted on a logarithmic scale and in panel C it is plotted on a linear scale. Open circle, solid line is mean data in asthmatics. Solid circle, dashed line is mean data in patients with chronic obstructive pulmonary disease. X, interrupted line is mean data from normal subjects. The curves were drawn using mean data from tables 3, 4, and 5.
reason for this is not apparent. It was not due to hypoxia; all subjects were rebreathing 93 per cent 0 2 at the time P 0 . 1 were measured. The mean arterial bicarbonate concentration was normal in the COPD patients (table 1), so arte· rial pH was probably little different from that of normal subjects at the same PAco 2 • It is possible that the increased P 0 . 1 represented a response to airway obstruction; this will be discussed subse· quently. Both on the first and second studies the asth· matics showed low values of ilVEfilPAco 2 • Rebuck and Read (13) found similar values in asthmatics during acute exacerbations; they followed their patients and found that in most, ilVEfilPAco 2 increased. vVe did not observe such an increase, but our subjects' degree of improvement of FEV1 was not as large as theirs. The asthmatics also demonstrated low values of b, but as indicated in figure 8 their absolute P 0 . 1 increased with C0 2 at least as much as that of the normal subjects. The most striking result of these experiments was the high P 0 . 1 demonstrated by the asthmatics. We presented data gathered at PAco 2 of 60 mm Hg, but similar conclusions could have been drawn by comparing P 0 . 1 at other values of PAco 2 ; P 0 . 1 values were high in asthmatics at all values of PAco 2 (figures 3, 6, and 8). Although we did not measure FRC in most of the asthmatics,
we do not believe that the P 0 . 1 values we observed were due to change in FRC. Exacerbations of asthma are accompanied by increases in FRC, which should decrease P 0 . 1 . Indeed, we showed that FRC values were increased in 5 subjects at the time of their first study and were less at the time of the second study, when P 0 . 1 decreased. Ten of the 12 asthmatics had measurements of arterial bicarbonate at the time of the first study ranging from 21 to 28 mEq per liter (mean, 24 mEq per liter), so it is unlikely that the high values of P 0 . 1 observed were due to acidosis. Except for corticosteroids, our asthmatics' drug regimens were similar to those of our patients with COPD, and we doubt that corticosteroids could explain the observed differences in P 0 . 1 . It is possible that the high P 0 . 1 values we observed in asthmatics represented a response to airway obstruction. P 0 . 1 decreased in the asthmatics when obstruction decreased, and there was a quantitative relationship between the increase in FEV1 and the decrease in P 0 . 1 (figure 7). Normal subjects have demonstrated increased P 0 . 1 while inspiring through external resistances (68), and increased activity of inspiratory intercostal muscles has been noted in response to artificial inspiratory obstruction (14, 15). However, comparing external inspiratory resistance in normal subjects with exacerbations of disease in asthmatics is difficult. Such comparison
926
ZACKON, DESPAS, AND ANTHONISEN
neglects the fact that the added resistive pressure drop is located in different airways and does not consider numerous other influences, such as bronchial irritant receptors, which may alter inspiratory muscle activity in asthma. Our patients with COPD also demonstrated ,-:dues of P 0 _1 that were greater than those of our normal subjects. These results also might have represented a response to airway obstruction. The fact that P 0 _1 values in patients with COPD were less than those in the asthmatics could indicate that the response to chronic obstruction is less than the response to acute obstruction . .-\ltcrnatively, our asthmatics probably had more severe airway obstruction than did our patients with COPD. Although both groups exhibited similar values of FEVv loss of lung recoil presumably contributed more to this measurement in the patients with COPD. Thus, if the increase in P 0 _1 were a response to increased airway resistance, one might have expected greater values of P 0 _1 in our asthmatics. It must be noted that these arguments rest on the unproved assumptions that the airway obstruction of asthma and COPD are similar and that effects of asthma and COPD on inspiratory muscle activity are chiefly dependent on the severity and duration of airway obstruction. Finally, if the high P 0 _1 values of COPD patients were due to obstruction per se, one would expect P 0 _1 to increase ils obstruction increased, especially if the obstruction were acute. It has been shown that, in contrast to normal subjects, added external inspiratory resistance produced no augmentation of P 0 _1 in patients with COPD (16). The absence of this response to acute resistance increase makes it unlikely that the elevated P 0 _1 values we observed were due to chronic increases in resistance. \Vhatever the reason, both asthmatics and patients with COPD demonstrated increased values of P 0 _1 at P Aco 2 of 60 mm Hg. This indicated that these patients had increased inspiratory muscle activity that was not explicable on the basis of C0 2 , 0 2 , or pH. It remains to be shown whether or not P 0 _1 accurately represented "ventilatory drive" or "ventilatory effort" in these patients. However, it is clear that at PAco 2 of 60 mm Hg the patients were utilizing a greater fraction of their total ventilatory capacity than the normal subjects. At P Aco 2 of 60 mm Hg, mean ventilation in the 3 groups was 23 to 28 liter per min. In the normal subjects this ventilation was a small fraction of maximum. If, for example, the average FEV 1 of our normal subjects was 4.0
liter, at PAco 2 of 60 mm Hg they were ventilating approximately 7 FEV1 per min. By contrast, at the same P Aco 2 , 5 of the patients with COPD and 6 of the patients with asthma had ventilations greater than 20 FEV 1 per min. Because 30 FEV1 per min is a useful approximation of the maximal breathing capacity (17), the ventilation achieved by these patients at PAco 2 of 60 mm Hg approached their maximum. It would be reasonable to suppose that attainment of such ventilatory levels was due to high levels of "ventilatory effort" or "ventilatory drive."
References I. Cherniack, R. M.: Work of breathing and the
ventilatory response to C0 2 , in Handbook of Physiology, sec. 3, Respiration, vo!. II, W. 0. Fenn and H. Rahn, ed., American Physiological Society, Washington, D.C. 1965, p. 1469. 2. Brodovsky, D., Macdonnel, J. A., and Cherniack, R. M.: The respiratory response to carbon dioxide in health and emphysema, J Clin Invest, 1960,39, 724. 3. Milic-Emili, J., and Tyler, J. M.: Relation between work output of respiratory muscles and end-tidal C0 2 tension, J Appl Physiol, 1963, 18,497.
4. Rebuck, A. S., and Pengelly, L. D.: Mechanical and chemical loads to the breathing system, in Loaded Breathing, L. D. Pengelly, A. S. Rebuck, and E. J. M. Campbell, ed., Longman Canada Ltd., Don Mills, Ontario, 1974, p. 10. 5. Whitelaw, W. A., Derenne, J.P., and Milic-Emili, J .: Occlusion pressure as a measure of respiratory center output in conscious man, Respir Physiol, 1975,23, 181. 6. Kryger, M. H., Yacoub, 0., and Anthonisen, N. R.: Effect of inspiratory resistance on occlusion pressure in hypoxia and hypercapnia, Respir Physiol, 1975,24,241. 7. Altose, M.D., Kelson, S. G., and Cherniack, N. S.: Effects of transient flow resistive loading and unloading in inspiratory muscle force, Physiologist, 1975,18, 120. 8. Shekleton, M., LaFata, J., Lapata, M., Evanich, M., and Louren~o, R. V.: Comparison of the effects of elastic and resistive loading on mouth occlusion pressure during C0 2 rebreathing (abstract), Clin Sci, 1975,23, 352a. 9. Bates, D. V., Macklem, P. T., and Christie, R. V.: Respiratory Function in Disease, ed. 2, W. B. Saunders, Philadelphia, 1971. p. 93. 10. Read, D. J. C.: A clinical method for assessing ventilatory response to carbon dioxide, Australas Ann Med, 1967, 16, 20. 11. Siegel, S.: Non-Parametric Statistics, McGrawHill, New York, 1956. 12. Maranetra, M., and Pain, M. C. F.: Ventilatory
OCCLUSIO~
PRESSURE RESPONSES IN ASTHMA AND COPD
drive and ventilatory response during rebreathing, Thorax, 1975,29,578. 13. Rebuck, A. S., and Read, J.: Patterns of ventilatory response to carbon dioxide during recovery from severe asthma, Clin Sci, 1971, 41, 13. 14. r\ewsom-Davis, J., Sears, T. A., Stagg, D., and Taylor, A.: The effects of airway obstruction on the electrical activity of intercostal muscles in conscious man, J Physiol (Lond), 1966, 185, 19p. 15. Shannon, R., and Zachman, F. W.: The reflex and mechanical response of the inspiratory mus-
927
des to an increased airflow resistance, Respir Physiol, 1972,16,51. 16. McCauley, W. C., Altose, M. D., Kelsen, S. G., and Cherniack, N. S.: The effects of airflow obstruction on respiratory neuron efferent activity in normal subjects and in patients with chronic obstructive lung disease, Am Rev Respir Dis, 1975,111,907. 17. Bates, D. V., Macklem, P. T., and Christie, R. V.: Respiratory Function in Disease, ed. 2, W. B. Saunders, Philadelphia, 1971. p. 22.
SUMMARY ___________________________________________ _______________ During C0 2 rebreathing we measured ventilation and the pressure generated during the first 0.1 sec of inspiratory effort against a closed airway (P 0 . 1 ) in 12 asthmatics during acute exacerbation, 10 nmmal subjects, and 10 patients with chronic obstructive pulmonary disease. In normal subjects, the ventilatory response to C0 2 correlated with the P 0 . 1 response measured as ~In P 0 . 1 . Patients with chronic obstructive pulmonary disease showed depressed responses to C0 2 in terms of both ventilation and ~In P 0 . 1 . However, P 0 . 1 values in the patients with chronic obstructive pulmonary disease were greater than those of the normal subjects when they were compared at an alveolar Pco 2 of 60 mm Hg. Asthmatics' responses to C0 2 were similar to those of patients with chronic obstructive pulmonary disease. When measured at an alveolar Pco 2 of 60 mm Hg, asthmatics' P 0 . 1 values were greater than those of both normal subjects and patients with chronic obstructive pulmonary disease. As the asthmatics' airway obstruction decreased so did their P 0 . 1 . The asthmatics, and to a lesser extent the patients with chronic obstructive pulmonary disease, demonstrated increased inspiratory muscle activity that could not be explained on the basis of chemical drive or alterations in functional residual capacity. In the case of the asthmatics it was possible that the increased inspiratory muscle activity was a 1·esponse to airway obstruction.
Introduction Since the observation that patients with chronic obstructive pulmonary disease (COPD) showed little increase in ventilation in response to inhaled C0 2 , the nature of ventilatory control in disease has been controversial. Lack of ventilatory response to C0 2 has been interpreted as loss of chemoceptor sensitivity (l). However, Brodovsky and co-workers (2) showed that ventila(Received in original form September 10, 1975 and in revised form August 6, 1976) 1 From the Respiratory Division, Royal Victoria Hospital, and the Montreal Chest Hospital Centre, McGill University, Montreal, Quebec, Canada. 2 Supported by the Medical Research Council of Canada and Quebec. 3 Requests for reprints should be addressed to Dr. N. R. Anthonisen, Respiratory Division, F-2 General Centre, Health Sciences Centre, 700 William Avenue, Winnipeg, Manitoba, Canada. 4 Fellow of the Quebec Medical Research Council.
tory responses were to some extent dependent on lung mechanics and that in disease a "normal"..-increase in respiratory muscle activity would provide a less than normal increase in ventilation. The issue was not how much the diseased patient breathed but how hard he or she was trying to breathe. Milic-Emili and Tyler (3), studying normal subjects breathing C0 2 with and without added external resistance, found that alveolar Pco 2 (P Aco 2) was uniquely related to inspiratory work rate and suggested that inspiratory work rate was a useful index of neural output to the respiratory muscles. Inspiratory work rate is difficult to measure, however, and there have been suggestions that during elastic loading inspiratory work rate was not uniquely related to PAco 2 (4). Recently, Whitelaw and associates (5) indicated that inspiratory muscle output may be quantitatively reflected by P O.l' the pressure developed at the mouth during the first 0.1 sec of inspiratory effort against an occluded airway. This measurement, because it is
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 114, 1976
917
918
ZACKON, DESPAS, AND ANTHONISEN
TABLE 1 1-SEC FORCED EXPIRATORY VOLUME (FEV 1 )/FORCED VITAL CAPACITY (FVC) FOR ASTHMATICS IN THE PRESENT STUDY AND THE BEST AND WORST VALUES FOR THE PRECEDING 3 YEARS
Subject
Age (years)
Sex
Car Aud Roy Tur Lon Sou Med Gos Hec Lap Cro Mih
68 35 27 39 80 44 68 48 53 43 64 45
M F F F F M M M F F M M
FEV 1 /FVC (/iter)
Predicted Normal Vital Capacity (/iter)
Present
3.8 3.4 3.1 3.6 2.5 4.8 4.0 3.9 3.8 3.1 3.5 4.5
static, shou!d not be influenced by the compliance or resistance of the respiratory system; it also should not be affected by volume-related vagal influences (5). Several groups (6-8) have shown that in normal subjects P 0 _1 was increased by added inspiratory resistance, indicating that acute increases in resistance may be ac-
Best
Worst
Study (First)
2.0/4.2 3.0/4.2 3.0/3.6 3.1/4.6 1.5/1.9 4.0/6.0 2.5/4.6 3.6/5.2 2.5/3.0 1.5/2.6 2.6/4.1 2.8/4.6
0.6/1.8 0.7/1.8 0.6/1.1 0.5/0.8 0.5/1.1 1.1/3.0 0.8/2.9 0.7/2.3 0.5/1.0 0.6/1.2 0.8/2.4 0.5/1.0
1.2/3.6 1.9/1.9 1.8/3.1 0. 7/2.4 1.0/1.6 1.8/3.5 0.8/3.3 2.1/3.4 1.7/2.3 1.0/1.9 1.3/3.2 1.8/3.9
companied by increased inspiratory muscle output. To determine if this finding has relevance in disease, we measured P 0 _1 in a group of asthmatics during exacerbations of their illness. Materials and Methods Twelve asthmatics were studied during hospitaliza-
TABLE 2 PULMONARY FUNCTION TEST VALUES AND PREDICTED NORMAL VALUES (IN PARENTHESES) IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (/iter)
vc
FRC (/iter)
1.6
2.8 (4.1)
5.0 (3.5)
4.0 (2.1)
44
26
M
1.1
2.5 (3.4)
4.5 (3.4)
3.5 (2.3)
39
24
54
M
1.1
2.9 (3.5)
5.0 (3.5)
3.6 (1.9)
38
24
Win
73
M
1.3
1.8 (3.7)
4.9 (3.8)
4.1 (2.5)
39
25
Dee
30
M
2.2
3.7 (5,2)
5.1 (4.0)
3.1 (2.0)
67
40
24
Tre
55
M
1.3
2.2 (3.5)
4.6 (3.1)
4.1 (1.9)
60
45
27
Niz
68
M
0.9
2.1 (3.1)
3.6 (3.0)
3.0 (2.0)
75
41
26
Mai
55
M
1.7
3.2 (3.1)
5.1 (3.2)
3.8 (2.2)
83
36
25
Rae
64
M
2.3
4.1 (3.7)
63
37
20
Mak
68
M
0.6
2.2 (3.3)
64
42
26
Subject
Age (years)
Sex
FEV 1 (/iter)
Gui
49
M
Cam
71
Lus
5.1 (3.3)
RV (/iter)
4.1 (2.2)
Hco;) Pao 2 Paco 2 (mm Hg) (mm Hg) (mEq/liter)
67
Definition of abbreviations: FEVr =forced expiratory volume in 1 sec; VC =vital capacity; FRC =functional residual capacity; RV = residual volume; Pao 2 = arterial 0 2 tension; Paco 2 = arterial C0 2 = tension; HC03 = bicarbonate.
919
OCCLUSION PRESSURE RESPONSES IN ASTHMA AND COPD
tion for acute exacerbations of their illness. All had been followed for at least 3 years with spirometric tests, and within that time all had demonstrated virtually normal function. Values of !-sec forced expiratory volume (FEV 1 ) measured at the time the patients were studied are compared in table l with the best and worst values that had been recorded during the preceding 3 years. None had chronic cough and sputum and all had experienced acute exacerbations in the absence of clinical evidence of respiratory infection. All were studied after recovery from the acute episode had begun. All were taking oral aminophylline preparations and inhaled B 2 stimulants, and most were taking oral corticosteroids. Ten normal men 26 to 36 years of age were also studied, 2 of whom had had previous experience as experimental subjects. Ten patients with COPD were also studied. These patients had been followed for more than a year, had chronic cough, sputum, and dyspnea, and were not subject to acute exacerbations of their symptoms in the absence of respiratory infections. None had C0 2 retention. All were regarded as stable by their physicians. This impression was supported by measurements of vital capacity and FEV 1 carried out on the day of the study; these results were the same as those of similar measurements made at least a month earlier. All of these patients were taking inhaled B 2 stimulants, and most were also taking aminophylline orally. Pulmonary function test values in these patients and predicted normal yalues (9) are shown in table 2. Lung volumes were determined by spirometrv and helium dilution, arterial blood gas values by appropriate electrodes. Subjects were studied in the seated position while rebreathing from a 6-liter bag containing 93 per cent 0 2 and 7 per cent C0 2 , as described by Read (10). The breathing circuit was modified so as to contain a breathing valve separating inspired and expired gas. Circuit resistance was 1.5 em H 2 0 per liter • sec and linear to 4 liter per sec. The expired line was sampled by an infrared C0 2 meter (Godart) at a rate of 1.0 liter per min, and this gas returned to the circuit. The inspiratory line contained a short length of compliant rubber tube in a plastic box. Mouth pressure was measured by a strain gauge (Sanborn 267B) connected to a needle that pierced the mouth· piece. The rebreathing bag was encased in a box and ventilation was measured by spirometrically recording box volume. Ventilation and mouth pressure were recorded on an oscillograph (Sanborn) at paper speeds of 50 mm per sec during occlusion. C0 2 concentrations were recorded as a function of time on another recorder (Beckman) with a 10-inch span. After familiarizing themselves with the equipment, subjects rebreathed from the circuit for at least 4 min. The inspired line was occluded during expiration at intervals of approximately 30 sec. The single occlusion never lasted longer than a single inspira-
tion and usually less. The subjects could neither see nor hear the occlusion, and the timing of the occlusions was varied enough so that subjects could not predict when occlusions would occur. During the same laboratory session both asthmatics and patients with COPD underwent duplicate measurements of FEV 1 , and in 5 of the asthmatics functional residual capacity (FRC) was also measured by plethysmography. One or more days after the initial experiment, studies were repeated in the asthmatics. In 9 of them the FEV 1 had increased by at least 0.3 liter over that measured at the time of the first study. In the other 3 patients the FEV 1 at the time of the second study was within 0.1 liter of that measured during the first study. Two normal subjects and 3 patients with COPD were also restudied in similar fashion. Ventilatory responses were analyzed by computing (least squares method) the slope of the response curve AVE/ APAco 2 , where VE is minute ventilation. The increase in P 0 _1 with PAco 2 was often not linear. To analyze our P 0 _1 -PAco 2 curves we followed the suggestion of Whitelaw and associates (5), who expressed these curves in the form InP 0 _1 =bPAco 2 +a. We computed b for each subject by the least squares method; increasing values by b therefore represented, in terms of P 0 _1 , increasing sensitivity to C0 2 . In our subjects, correlation coefficients between hJ
80
Des
0
•
Par
0
• 0
0.
•
0
•
P0.1 16 cm~O
12 8 4
0
0 0 0
•• •
•
•
0
60
80 80 PAc02 ,mmHg
80
Fig. l. Ventilatory and Po. 1 responses in 2 normal subjects (Des and Par) studied on 2 occasions. Upper panels show minute ventilation (VE) as a function of alveolar .Pco 2 (PAco 2 ); the lower panels show Po. 1 as a function of C0 2 • Open circles represent results of the first study, closed circles the results of the second.
920
ZACKON, DESPAS, AND ANTHONISEN
Njz
Tre
Mai
~ • 0
0
P0.1 c:mH2o
0 0
o. o.
0
•
•
0
50
•
~·
80
70
80
50
PAc02 ,mmHa Fig. 2. Ventilatory and Po. 1 responses in 3 subjects with chronic obstructive pulmonary disease studied on 2 occasions. Upper panels show minute ventilation (VE) as a function of alveolar Pco2 (PAco 2 ); the lower panels show Po.l as a function of PAco 2 • Open circles are results of the :first study, closed circles the results of the second. PO.l and PAco 2 were significantly better (P < 0.05 by paired t test) than those between P 0 . 1 and PAco2 . These analyses expressed responses to changes in PAco 2 . We also compared ventilatory and P 0 . 1 responses at a fixed level of C0 2 , PAco 2 of 60 mm Hg. This value was chosen because it was encom-
Mih
VE
eo
40
L/mi~
0
•
0i0.
0
i
•
Cro
Lap
o.o.
o o••
o•
passed by response curves in all subjects, so that ventilation and P 0 . 1 at PAco 2 of 60 mm Hg could be derived by interpolation rather than extrapolation. Results for each group of subjects were averaged, and when variances were equal, the means were compared by t test; this was seldom the case, however.
ia. • i
0
.o
.,
0
0
3 •
0
16
P0.1
0
oo
anH~ 0
0
0
0
•
12
4
• •
0
•o•
0.
•
••o eo
•
e•
•
0
oe
0
oe
0
oe
0
oed'
50
70
80
80
80
10
PAc02 ,mmHg Fig. 3. Ventilatory and Po. 1 responses in 3 asthmatics who were studied on 2 occasions when their 1-sec forced expiratory volume differed by .;;; 0.1 liter. Upper panels show ventilatory responses to alveolar Pco2 (PAco 2); lower panels show Po. 1 responses to PAco 2• Open circles are the results of the first study, closed circles the results of the second.
921
OCCLUSION PRESSURE RESPONSES IN ASTHMA AND COPD
TABLE 3 RESPONSE TO C0 2 REBREATHING IN NORMAL SUBJECTS Po.t t
VEt
Subject
(liter/min • mm Hg)
b*
(em H 2 0)
(/iter/min)
Nus Rah Par Sou Des Kar Bru Ott Hor Fri Mean SD
4.0 1.2 1.2 0.4 4.6 1.0 3.3 10.0 4.3 2.3 3.2 0.3
0.128 0.065 0.061 0.066 0.111 0.095 0.097 0.195 0.206 0.078 0.110 0.052
4.0 4.0 1.5 0.5 3.0 3.0 3.0 8.0 1.5 2.0 3.0 2.1
40 22 20 13 35 27 21 57 40 10 28.5 14.0
AVE/A PAco 2
alveolar C02 ten· Definition of abbreviations: \IE = minute ventilation; PAcoz sion; Po. 1 = pressure during the first 0.1 sec of inspiratory effort against an occluded airway. • From In P 0 • 1 = b PAco 2 +a. tAt PAco 2 of 60 mm Hg.
When variances were unequal, mean values were compared by the Wilcoxon-Mann·Whitney (WMW) test (11). Results Examples of ventilatory and P 0 _1 responses to C0 2, each done in duplicate, are shown in figures 1 to 3. Figure 1 shows results of 2 studies in normal subjects, figure 2 show~ similar results in 3 patients with COPD, and figure 3 shows results in the 3 asthmatics in whom the FEV1 changed by 0.1 liter or less. In all cases, results of first and second studies differed little. Responses in our normal subjects are summarized in table 3. Ventilatory responses (A"VE/ tiP Aco 2) averaged 3.2 liter per min· mm Hg, but varied widely in this group, ranging from 0.4 to 10.0 liter per min • mm Hg. Values forb varied less, their mean being 0.11 0. There was a correlation (r 0.81, P < 0.01) between t'lVE/ t'lPAco 2 and b (figure 4), indicating that subjects in whom C0 2 induced large changes of ventilation also showed relatively large changes of P 0 . 1 . At PAco 2 of 60 mm Hg, P 0 . 1 averaged 3.0 em H 2 0 and mean ventilation was 28.5 liter per min. Ventilatory responses of the patients with COPD are summarized in table 4. Values for t'lVEjtlPAco 2 were low, averaging 1.0 liter per min • mm Hg. This was significantly less (P < 0.05, WMW) than those found in the normal subjects. Values of b in the patients with COPD averaged 0.065, which was also significantly less (P < 0.05 WMW) than those of normal subjects. Among patients with COPD there was no corre-
lation between band LlVEjtlPAco 2 . At PAco 2 of 60 mm Hg, VE did not differ from that observed in normal subjects, but P 0 . 1 averaged 4.8 em H 2 0, higher (P < 0.05, WMW) than the value found in normal subjects. P 0 . 1 values at PAco 2 of 60 mm Hg are shown for normal subjects and patients with COPD in figure 5. Asthmatics' responses are summarized in table 5. The initial ventilatory responses to C0 2 were similar to those of tl1e patients witll COPD, averaging 1.3 liter per min • mm Hg. However, LlVE/ tlPAco2 tended to vary more in the asthmatics, b
• •
=
•
•
•
2
4 ~-
VE/6PAco2
Fig. 4. Correlation between ventilatory and Po. 1 re· spouses to C0 2 in normal subjects. Abscissa shows slope of ventilatory response to alveolar Pco 2 ( PAco 2 ); ordinate shows slope of the relationship of In Po. 1 to PAco2 (b = Llln Po. 1 /APAco2). Each point represents a normal subject.
922
ZACKON, DESPAS, AND ANTHONISEN
TABLE 4 RESPONSE TO C0 2 REBREATHING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE Po.t
.O.VE/.O.PAco 2
Subject
(/iter/min • mm Hg)
Gui Cam Lus Win Dee Tre Niz Mai Rae Mak Mean SD
0.5 1.2 1.2 0.3 0.6 1.6 0.8 0.8 2.1 0.9 1.0 0.5
b 0.024 0.105 0.062 0.041 0.034 0.092 0.066 0.082 0.072 0.074 0.065 0.026
.
VE •
(em H 2 0)
(/iter/min)
3.0 3.0 6.0 4.0 3.0 7.0 5.5 4.5 5.5 6.5 4.8 2.3
18 13 25 18 22 36 18 19 50 19 23.8 11.0
*At PAc02 of 60 mm Hg. For definition of abbreviations, see table 3.
and their mean !iVE(!iPAco2 did not differ from that of the normal subjects. Initial value for b was 0.061, similar to that of patients with COPD and less (P < 0.05 WMW) than that of the normal subjects. There was no correlation between values of !iVE(!iPAco2 and values of b. On their initial study the asthmatics showed large P 0 . 1 values at PAco 2 of 60 mm Hg (figure 5). The average value was 12.4 em H 2 0, significantly greater than that of normal subjects (P < 0.001, WMW) and of patients with COPD (P < 0.01, WMW). Ventilation at PAco2 of 60 mm Hg did not differ among the 3 groups. On repeat study, 9 of the asthmatics demonstrated an increase in FEV1 of at least 0.3 liter. In these patients !iVE(!iPAco2 changed in unpredictable fashion, as did b. However, P 0 . 1 at PAco 2 of 60 mm Hg decreased in all 9 subjects (table 5), whereas ventilation did not change consistently. Complete response curves in 3 of these patients are shown in figure 6. There was little change in P 0 . 1 at PAco 2 of 60 mm Hg in the 3 asthmatics who showed little change in FEV1 (table 5; figure 3). When first and second studies of all our asthmatics were considered, there was a significant correlation (r = 0.67; P < 0.02) between the per cent increase in FEV1 and the per cent decline in P 0 . 1 at PAco 2 of 60 mm Hg (figure 7). FRC was initially increased in the 5 patients in whom it was measured, and in 4 of them it had decreased at the time of the second study. Mean data from tables 3, 4, and 5 are represented graphically in figure 8; only the first study of the asthmatics is shown. Although figure 8 was constructed by combining mean values for
!iVE(!iPAco 2 and b with mean VE and l'0 . 1 at PAco 2 of 60 mm Hg, the resulting curves give accurate representations of mean VE and mean P 0 . 1 at PAco 2 of 55 mm Hg and 65 mm Hg. Ventilatory response was greatest in normal subjects, with results in asthma and COPD differing little (figure SA). P 0 . 1 responses are shown in 2 ways, on a loga.rithmic scale (figure SB) and an algebraic one (figure BC). It can be seen that In P 0 . 1 increased more rapidly in normal subjects as indicated by the relatively large values for b in table 3. However, in our asthmatics and patients with COPD, P 0 . 1 values at low PAco 2 were high. Therefore, although these patients had low values for b, their absolute increases in
p 0.1 PAco 2 =eo em H 2o
• •
•• •
.. I
•
L I
•• :.
-
N
COLD
•
•
•
•
ASTHMA
Fig. 5. Values for Po. 1 measured at alevolar Pco2 (PAco 2 ) of 60 mm Hg are shown for the first study of all subjects, grouped according to diagnosis. N normal; COLD "'chronic obstructive lung disease.
923
OCCLUSION PRESSURE RESPONSES IN ASTHMA AND COPD
TABLE 5 RESPONSE TO C0 2 REBREATHING IN PATIENTS WITH ASTHMA Subject
Study
FEV 1/FVC
FRC
(liter)
(liter)
VE/PAco 2 (liter/min • mm Hg)
6.0 5.4
1.2 1.4
Cor
2 2
1.2/3.6 1.5/4.2
Aud
2 2
0.9/1.9 1.7/2.9
Roy
2 2
Tur
2 22 2 22 2 212 21 22
1.8/3.5 2.2/3.7
Gas Hec
b
.
Po.t (em H 2 0)
VE* (/iter/min)
11.0 6.0
30 28
0.7 1.9
0.087 0.080 0 0.060
22.0 9.0
28 38
1.8/3.1 2.2/3.4
1.5 0.8
0.086 0.097
25.5 9.0
29 22
0.7/2.4 1.2/3.6
0 0.8
0.050 0.045
17.0 7.0
17 20
1.0/1.6 1.7/2.0
1.5 1.1
0.074 0.033
11.5 6.0
30 28
5.9 4.9
1.4 1.8
0.091 0.074
3.0 2.0
23 18
0.8/3.3 1.5/3.8
5.5 5.5
1.2 1.1
0.068 0.073
4.5 3.0
20 24
2 22
2.1/3.4 2.8/5.2
5.2 4.8
2.0 2.0
0.078 0.106
18.0 10.0
64 40
2 22 121 2121 212
0.7/2.3 1.4/3.2
5.2 3.9
0 1.0
0.057 0.050
16.0 7.0
22 22
1.011.9 1.1/1.8
0.8 0.7
0.033 0.024
7.0 8.0
14 16
22
1.3/3.2 1.3/3.2
1.4 1.4
0.044 0.047
22 21
Min
2 22
1.8/3.9 1.9/3.8
1.4 1.5
0.061 0.069
6.5 6.0 7.0 7.0
Mean
2 21 122
1.3/2.8 0.5 0.6
1.1 0.6
0.061 0.026
12.4 7.2
26.7 12.7
1.7/3.4 0.5,0.9
1.3 0.4
0.063 0.026
6.8 2.4
25.2 7.4
Lon Bou Med
Lap Cro
so
Mean
so
25 28
• At PAco 2 of 60 mm Hg. For definition of abbreviations, see tables 2 and 3.
P 0 . 1 with PAco 2 were comparable to those of nor mal subjects (figure 8C). Discussion
In comparing our 3 subject groups, it should be noted that there were obvious nonrespiratory differences among them. The normal group was younger than either the asthmatics or the patients with COPD. Furthermore, half the asthmatics were female, whereas all other subjects studied were male. It is possible that these differences influenced our results. We have measured P 0 _1 in a few young normal women, andresults were similar to those in men (6; Unpublished observations). In the present study female asthmatics did not differ from male asthmatics. \Ve do not believe that sex differences were responsible for our results. To our knowledge no measurement of P 0 . 1 in older normal subjects has been reported, but we are unaware of any a priori reason for supposing that values
of P 0 . 1 should increase with age, and we are inclined to discount this possibility. There was no significant difference between the mean age of our asthmatics and the mean age of our patients withCOPD. Our results in normal subjects were very similar to those of Whitelaw and associates (5), who examined a similar group of subjects with the same technique. However, previous workers (5, 6) have been unable to show inter-individual correlation between ventilatory and P 0 .1 responses to C0 2 • This failure was believed to be due to inter-individual differences in the relationship between VE and P 0 .1 . Comparing ventilatory and P 0 . 1 responses to C0 2 is equivalent to examining the relationship between VE and P o.I> and if this relationship varies substantially among individuals, correlations of ventilatory and P 0 . 1 responses to C0 2 will be poor. We found (figure 4) a significant inter-individual correlation between ventilatory and P 0 . 1 responsiveness.
924
ZACKON, DESPAS, AND ANTHONISE:-.1
Aud
Hec
Ve
•
Lfmin
0
0
•
i •
Roy
••
••
•o o
0
o
• •aao •
0
o•o • ooe
o~.----------r--
40 0
P0.1 em H20
32
0
0
24 16
0 0 0
•• 0
0
0 0
50
•
0
0
0
0
00
0
• ••
0
• • • •• •
70
••
0
••
..
•• •
•
50
70
50
0
0
PAc 02 ,mmHg
Fig. 6. Ventilatory and Po. 1 responses to C0 2 in 3 asthmatics who demonstrated less airway obstruction (increase of 1-sec forced expiratory volume of at least 0.3 liter) at the time of the second study (closed circles) than they did in the first (open circles). Upper panels are ventilatory responses to C0 2 ; lower panels are P0. 1 responses. This may have been because our normal group showed a greater range of values for both AVE/ ~PAco 2 and b than did groups examined in previous studies. The presence of extreme values probably helped in establishing a relationship. Our patients with COPD demonstrated low values of AVEjAPAco 2 , as expected (1). They also demonstrated low b. However, figure 8 illustrates that decreased values for b do not necessarily mean that the absolute increase in P 0 _1 was Jecrea,ed. Indeed, the absolute increase in P 0 _1 with C0 2 in our patients with COPD was only slightly diminished (figure 8C). This finding was in agreement with those of Maranetra and Pain (12), who, using a different occlusion technique, found no difference in change of occlusion pressure with PAco 2 between normal subjects and patients with COPD. It is clear that there are serious objections to considering the relatively low b found in patients with COPD as indicative of reduced P 0 _1 responses in these patients. The lack of correlation between b and ~ VE j APAco 2 was not surprising because the presence of such a correlation would have implied a similar relationship between VE and P 0 _1 among these patients. Lung mechanics varied among the patients and presumably affected VE more than P 0 _1 •
P 0 _1 values measured at PAco 2 of 60 mm Hg were greater in our COPD patients than in our normal subjects. FRC was increased in the COPD patients (table l ), and other things being equal, increases in FRC should decrease P 0 . 1 (5). We therefore concluded that at PAco 2 of 60 mm Hg our COPD patients demonstrated increased activity of the inspiratory muscles. The 6FEV1.0
-2o
o
20
,"fo
4o
60
ao
100
·2~---L--~--~--~--~~
6P0.1 -20 ..._co2·60 -40
"'o
..
-60 -10 -1
Fig. 7. Correlation between change in 1-sec forced expiratory volume (FEV d and change in Po. 1 in the asthmatics. Ordinate shows change in Po. 1 measured at alveolar Pco 2 (PAco 2 ) of 60 mm Hg, expressed as a percentage of the value noted during the initial study. Abscissa shows change in FEV 1 expressed as a percentage of the FEV 1 measured at the time of the first study. Each point represents an asthmatic patient.
925
OCCLUSIO)>.[ PRESSURE RESPO"'SES IN ASTHMA AND COPD
•
A
I
VE L/mW..
I
.I
p 0.1
, '
,
I
I
I
PO.l em H2 0
cm~O
/
I
c
. 'I
,•'/
..w'./
I
_,,j
I
/1
/
/
oL-~----r---~-
50
60
70
60
50
70
0
50
--··? -
-·
60
70
PAC02 mmHg
Fig. 8. Mean C0 2 response curves of the 3 groups studied; the asthmatics' second study is not shown. In panel A, ventilation is plotted against alveolar Pco 2 . In panel B, Po. 1 is plotted on a logarithmic scale and in panel C it is plotted on a linear scale. Open circle, solid line is mean data in asthmatics. Solid circle, dashed line is mean data in patients with chronic obstructive pulmonary disease. X, interrupted line is mean data from normal subjects. The curves were drawn using mean data from tables 3, 4, and 5.
reason for this is not apparent. It was not due to hypoxia; all subjects were rebreathing 93 per cent 0 2 at the time P 0 . 1 were measured. The mean arterial bicarbonate concentration was normal in the COPD patients (table 1), so arte· rial pH was probably little different from that of normal subjects at the same PAco 2 • It is possible that the increased P 0 . 1 represented a response to airway obstruction; this will be discussed subse· quently. Both on the first and second studies the asth· matics showed low values of ilVEfilPAco 2 • Rebuck and Read (13) found similar values in asthmatics during acute exacerbations; they followed their patients and found that in most, ilVEfilPAco 2 increased. vVe did not observe such an increase, but our subjects' degree of improvement of FEV1 was not as large as theirs. The asthmatics also demonstrated low values of b, but as indicated in figure 8 their absolute P 0 . 1 increased with C0 2 at least as much as that of the normal subjects. The most striking result of these experiments was the high P 0 . 1 demonstrated by the asthmatics. We presented data gathered at PAco 2 of 60 mm Hg, but similar conclusions could have been drawn by comparing P 0 . 1 at other values of PAco 2 ; P 0 . 1 values were high in asthmatics at all values of PAco 2 (figures 3, 6, and 8). Although we did not measure FRC in most of the asthmatics,
we do not believe that the P 0 . 1 values we observed were due to change in FRC. Exacerbations of asthma are accompanied by increases in FRC, which should decrease P 0 . 1 . Indeed, we showed that FRC values were increased in 5 subjects at the time of their first study and were less at the time of the second study, when P 0 . 1 decreased. Ten of the 12 asthmatics had measurements of arterial bicarbonate at the time of the first study ranging from 21 to 28 mEq per liter (mean, 24 mEq per liter), so it is unlikely that the high values of P 0 . 1 observed were due to acidosis. Except for corticosteroids, our asthmatics' drug regimens were similar to those of our patients with COPD, and we doubt that corticosteroids could explain the observed differences in P 0 . 1 . It is possible that the high P 0 . 1 values we observed in asthmatics represented a response to airway obstruction. P 0 . 1 decreased in the asthmatics when obstruction decreased, and there was a quantitative relationship between the increase in FEV1 and the decrease in P 0 . 1 (figure 7). Normal subjects have demonstrated increased P 0 . 1 while inspiring through external resistances (68), and increased activity of inspiratory intercostal muscles has been noted in response to artificial inspiratory obstruction (14, 15). However, comparing external inspiratory resistance in normal subjects with exacerbations of disease in asthmatics is difficult. Such comparison
926
ZACKON, DESPAS, AND ANTHONISEN
neglects the fact that the added resistive pressure drop is located in different airways and does not consider numerous other influences, such as bronchial irritant receptors, which may alter inspiratory muscle activity in asthma. Our patients with COPD also demonstrated ,-:dues of P 0 _1 that were greater than those of our normal subjects. These results also might have represented a response to airway obstruction. The fact that P 0 _1 values in patients with COPD were less than those in the asthmatics could indicate that the response to chronic obstruction is less than the response to acute obstruction . .-\ltcrnatively, our asthmatics probably had more severe airway obstruction than did our patients with COPD. Although both groups exhibited similar values of FEVv loss of lung recoil presumably contributed more to this measurement in the patients with COPD. Thus, if the increase in P 0 _1 were a response to increased airway resistance, one might have expected greater values of P 0 _1 in our asthmatics. It must be noted that these arguments rest on the unproved assumptions that the airway obstruction of asthma and COPD are similar and that effects of asthma and COPD on inspiratory muscle activity are chiefly dependent on the severity and duration of airway obstruction. Finally, if the high P 0 _1 values of COPD patients were due to obstruction per se, one would expect P 0 _1 to increase ils obstruction increased, especially if the obstruction were acute. It has been shown that, in contrast to normal subjects, added external inspiratory resistance produced no augmentation of P 0 _1 in patients with COPD (16). The absence of this response to acute resistance increase makes it unlikely that the elevated P 0 _1 values we observed were due to chronic increases in resistance. \Vhatever the reason, both asthmatics and patients with COPD demonstrated increased values of P 0 _1 at P Aco 2 of 60 mm Hg. This indicated that these patients had increased inspiratory muscle activity that was not explicable on the basis of C0 2 , 0 2 , or pH. It remains to be shown whether or not P 0 _1 accurately represented "ventilatory drive" or "ventilatory effort" in these patients. However, it is clear that at PAco 2 of 60 mm Hg the patients were utilizing a greater fraction of their total ventilatory capacity than the normal subjects. At P Aco 2 of 60 mm Hg, mean ventilation in the 3 groups was 23 to 28 liter per min. In the normal subjects this ventilation was a small fraction of maximum. If, for example, the average FEV 1 of our normal subjects was 4.0
liter, at PAco 2 of 60 mm Hg they were ventilating approximately 7 FEV1 per min. By contrast, at the same P Aco 2 , 5 of the patients with COPD and 6 of the patients with asthma had ventilations greater than 20 FEV 1 per min. Because 30 FEV1 per min is a useful approximation of the maximal breathing capacity (17), the ventilation achieved by these patients at PAco 2 of 60 mm Hg approached their maximum. It would be reasonable to suppose that attainment of such ventilatory levels was due to high levels of "ventilatory effort" or "ventilatory drive."
References I. Cherniack, R. M.: Work of breathing and the
ventilatory response to C0 2 , in Handbook of Physiology, sec. 3, Respiration, vo!. II, W. 0. Fenn and H. Rahn, ed., American Physiological Society, Washington, D.C. 1965, p. 1469. 2. Brodovsky, D., Macdonnel, J. A., and Cherniack, R. M.: The respiratory response to carbon dioxide in health and emphysema, J Clin Invest, 1960,39, 724. 3. Milic-Emili, J., and Tyler, J. M.: Relation between work output of respiratory muscles and end-tidal C0 2 tension, J Appl Physiol, 1963, 18,497.
4. Rebuck, A. S., and Pengelly, L. D.: Mechanical and chemical loads to the breathing system, in Loaded Breathing, L. D. Pengelly, A. S. Rebuck, and E. J. M. Campbell, ed., Longman Canada Ltd., Don Mills, Ontario, 1974, p. 10. 5. Whitelaw, W. A., Derenne, J.P., and Milic-Emili, J .: Occlusion pressure as a measure of respiratory center output in conscious man, Respir Physiol, 1975,23, 181. 6. Kryger, M. H., Yacoub, 0., and Anthonisen, N. R.: Effect of inspiratory resistance on occlusion pressure in hypoxia and hypercapnia, Respir Physiol, 1975,24,241. 7. Altose, M.D., Kelson, S. G., and Cherniack, N. S.: Effects of transient flow resistive loading and unloading in inspiratory muscle force, Physiologist, 1975,18, 120. 8. Shekleton, M., LaFata, J., Lapata, M., Evanich, M., and Louren~o, R. V.: Comparison of the effects of elastic and resistive loading on mouth occlusion pressure during C0 2 rebreathing (abstract), Clin Sci, 1975,23, 352a. 9. Bates, D. V., Macklem, P. T., and Christie, R. V.: Respiratory Function in Disease, ed. 2, W. B. Saunders, Philadelphia, 1971. p. 93. 10. Read, D. J. C.: A clinical method for assessing ventilatory response to carbon dioxide, Australas Ann Med, 1967, 16, 20. 11. Siegel, S.: Non-Parametric Statistics, McGrawHill, New York, 1956. 12. Maranetra, M., and Pain, M. C. F.: Ventilatory
OCCLUSIO~
PRESSURE RESPONSES IN ASTHMA AND COPD
drive and ventilatory response during rebreathing, Thorax, 1975,29,578. 13. Rebuck, A. S., and Read, J.: Patterns of ventilatory response to carbon dioxide during recovery from severe asthma, Clin Sci, 1971, 41, 13. 14. r\ewsom-Davis, J., Sears, T. A., Stagg, D., and Taylor, A.: The effects of airway obstruction on the electrical activity of intercostal muscles in conscious man, J Physiol (Lond), 1966, 185, 19p. 15. Shannon, R., and Zachman, F. W.: The reflex and mechanical response of the inspiratory mus-
927
des to an increased airflow resistance, Respir Physiol, 1972,16,51. 16. McCauley, W. C., Altose, M. D., Kelsen, S. G., and Cherniack, N. S.: The effects of airflow obstruction on respiratory neuron efferent activity in normal subjects and in patients with chronic obstructive lung disease, Am Rev Respir Dis, 1975,111,907. 17. Bates, D. V., Macklem, P. T., and Christie, R. V.: Respiratory Function in Disease, ed. 2, W. B. Saunders, Philadelphia, 1971. p. 22.
