17

Journal of Physiology (1992), 455, pp. 17-32 With 5 figures Printed in Great Britain

THE EFFECT OF INSPIRATORY MUSCLE FATIGUE ON BREATHING PATTERN AND VENTILATORY RESPONSE TO C02

BY M. JEFFERY MADOR AND MARTIN J. TOBIN From the Division of Pulmonary Medicine, State University of New York at Buffalo, Veterans' Administration Medical Center, Buffalo, NY, and the Division of Pulmonary and Critical Care Medicine, Edward Hines Jr, Veterans' Administration Medical Center, Loyola University of Chicago Stritch School of Medicine, Hines, IL, USA

(Received 18 September 1991) SUMMARY

1. The effects of inducing inspiratory muscle fatigue on the subsequent breathing pattern were examined during resting unstimulated breathing and during CO2 rebreathing. In addition, we examined whether induction of inspiratory muscle fatigue alters CO2 responsiveness. 2. Global inspiratory muscle fatigue and diaphragmatic fatigue were achieved by having subjects breathe against an inspiratory resistive load while generating a predetermined fraction of either their maximal mouth pressure or maximal transdiaphragmatic pressure until they were unable to generate the target pressure. 3. Induction of inspiratory muscle fatigue had no effect on the subsequent breathing pattern during either unstimulated breathing or during CO2 rebreathing. 4. Following induction of inspiratory muscle fatigue, the slope of the ventilatory response to CO2 was significantly decreased from 18-8 + 33 during control to 13-8+221 1 min- (% end-tidal CO2 concentration)- with fatigue (P < 002). INTRODUCTION

Considerable interest has been focused on the effect of respiratory muscle fatigue on ventilatory control. It has been suggested that somatic afferents from fatiguing respiratory muscles may impinge on the central controllers and produce alterations in the breathing pattern during the fatiguing process and in the immediate recovery period (Roussos, 1984). Evidence to support this hypothesis has been obtained in anaesthetized (Road, Vahi, Del Rio & Grassino, 1987) and awake (Oliven, Lohda, Adams, Simhai & Kelsen, 1988) animals but less information is available in conscious human subjects. Recently, Gallagher, Im Hof & Younes (1985) observed rapid shallow breathing in healthy human subjects in the immediate recovery period following induction of inspiratory muscle fatigue. In addition, Moxham, Morris, Wiles, Newham, Spiro & Edwards (1982b) have suggested that the ventilatory response to carbon dioxide (CO2) is reduced following the development of fatigue. In contrast to the findings of Gallagher et al. (1985), we have observed tachypnoea MS 9747

A1. J. MADOR AND M. J. TOBIN

18

following induction of fatigue only in the presence of a markedly increased respiratory load (Mador & Acevedo, 1991 a, b). We hypothesized that fatigue alone in the absence of an increased respiratory load is not sufficient to alter the pattern of breathing in healthy human subjects. To test this hypothesis, we measured the breathing pattern during resting unstimulated breathing before and after induction of either global inspiratory muscle fatigue or diaphragmatic fatigue. In an additional experiment, we measured the ventilatory response to CO2 before and after the induction of inspiratory muscle fatigue to determine whether fatigue might reduce the ventilatory responsiveness to CO2. METHODS

ASubjects Three groups of healthy subjects volunteered for this study. The study

was

approved by the

appropriate Human Rights Committees and informed consent was obtained from all subjects. Experiment I

25-35

Six men and one woman, aged years (mean, 29 years), volunteered for this experiment. The subjects breathed through a two-way non-rebreathing valve of low resistance and dead space (Hans-Rudolph, Model 2600). Minute ventilation (V,), tidal volume (VT) and respiratory rate (fr) were measured with a turbine pneumotachograph. Expired gas was passed through a mixing chamber and anlysed for oxygen (02) and CO2 concentrations by a paramagnetic 02 analyser

(ADC,

Kent, UK)

and an infrared CO2 analyser (ADC), respectively. Both analysers

calibrated before each study with test

were

of known composition. The heart rate(ff) was determined from the electrocardiograph. Average values of VT,frL 02 uptake CO2 production(VPO) andf, were calculated every 15 s. In addition, in four of the subjects, expiredCO2 was sampled at the mouthpiece and analysed by a second infrared CO2 analyser (End TidIL 200 Instrumentation Laboratory, Lexington, MA, USA). Mouth pressure(Pm) was measured by a differential pressure transducer(Validyne, Northridge, CA, USA) connected to a mouthpiece. The pressure signals were recorded on a polygraph recorder (Hewlett-Packard 7758A) and displayed to the subject on an oscilloscope (Tektronic 2213, Beaverton, OR, USA). Pm max was measured during a maximum inspiratory effort against an occluded airway at functional residual capacity. At least three reproducible measurements were obtained in each subject. The values ranged from 111 to 139 cmH20 (mean 122 cmH 20). After 10 min of adaptation to the circuit, baseline measurements were recorded over the subsequent 10 min. The subjects were then instructed to breathe through an inspiratory resistive load while maintaining 80 % of the predetermined max Resistance was achieved by a screw clamp on a compressible tube which was adjusted at the start of each experiment to help the subject reach the required The remainder of the circuit tubing was of low compliance and the expiratory line was not loaded. The subject was instructed to maintain a constant Pm throughout inspiration as reflected by a square-wave pattern on the oscilloscope. Otherwise, he/she was allowed to choose his/her own breathing pattern and was given no special instructions as to how to achieve the target Pmm The subject received encouragement to maintain the target Pm in the desired fashion and to continue with the test. At the point when the subject could no longer sustain the target pressure, all of the inspiratory muscles including the diaphragm were considered to be fatigued (Roussos, Fixley, Gross & Macklei, 1979). The screw clamp was then immediately removed from the inspiratory line and the subject continued to breathe through gases

VI,

Pm

Pmm

the mouthpiece to permit data collection for

an

(VO2),

min.

additional 10

Experiment II We reasoned that

(Pii

subjects who generate a predetermined fraction of their maximal than their would develop more pronounced max) m,max fatigue of the diaphragm (Hershenson, Kikuchi, Tzelepis & McCool, 1989). Fatigue of the diaphragm may be particularly important in producing rapid shallow breathing (Road et al. 1987). transdiaphragmatic

In

this

breath.

experiment,

pressure

therefore

rather

requested

the subjects

to

generate

of their

pdi max

with

each

BREA THING PA TTERN AND FA TIG

19E 19

Eight men, aged 24-34 years (mean 29 years), volunteered for this study. Gastric (Pga) and oesophageal (Poes) pressures were measured by means of two thin-walled latex balloons, one positioned in the stomach and the other in the middle third of the oesophagus. Inspiratory flow was measured with a pneumotachograph (Hans-Rudolph, Kansas City, MO, USA) and the flow signal was integrated to measure changes in volume. We also sampled expired gas at the mouthpiece and analysed CO2 concentrations with a mass spectrometer (Perkin-Elmer, Pamona, CA, USA). The subject's Pdi, max was recorded while performing a combined Mueller expulsive manoeuvre against an occluded airway at functional residual capacity (Laporta & Grassino, 1985). During a Mueller-expulsive manoeuvre, the subject makes a maximal inspiratory effort while simultaneously contacting his/her abdominal muscles. Pa and poes were displayed on a storage oscilloscope (Gould) to aid the subject in reaching his pdi max At least three reproducible measurements were obtained in each subject. The values ranged from 125 to 222 cmH2O (mean 171 cmH2O). After 5 min of adaptation to the circuit, baseline measurements of the breathing pattern were recorded over the subsequent 5 min. The subjects were then instructed to breathe through an inspiratory resistive load (similar to experiment I) while maintaining 60% of the predetermined Pdi max A lower target pressure was employed in this experiment (60 vs. 80%) because sustainable Pdi (expressed as a percentage of maximum) is lower than sustainable Pm (Roussos & Macklem, 1977; Roussos et al. 1979). The Pdi signal was displayed on an oscilloscope (Gould) in front of the subject, and he attempted to maintain a constant PJi throughout inspiration as reflected by a square-wave pattern on the oscilloscope. Otherwise, he was allowed to choose his own breathing pattern. When the subject could no longer reach the target pressure, diaphragmatic fatigue was considered to have occurred and the inspiratory resistance was removed. Since it was observed in experiment I that the subjects hyperventilated for the first 2-3 min after removal of the resistive load, we allowed the subject to come off the mouthpiece for 3 min before the post-load breathing pattern was recorded for an additional 5 min. This allowed the breathing pattern to be measured at similar minute ventilations before and after loading. Experiment III (A) The purpose of this experiment was twofold: (1) to determine whether inspiratory muscle fatigue alters the ventilatory response to hypercapnia, and (2) to determine whether the induction of fatigue produces relative rapid shallow breathing during C02-stimulated breathing. Six men, aged 24-33 years (mean, 28 years), volunteered for this experiment. Responses to hypercapnia were measured by a modification of the Read technique (Read, 1967). The subject rebreathed 7 % CO2 in 02 from a 6-71 anaesthesia bag. Ventilation was measured by a turbine pneumotachograph attached to the inspiratory side of the mouthpiece. Expired gas was continuously sampled by an infrared CO2 analyser (ADC). The subject then rested for 20 min following which he breathed through an inspiratory resistive load while maintaining 80% of the predetermined Pm max in a fashion identical to experiment I and II. Following the fatigue run, the subject rested for 20 min before undergoing another period of CO2 rebreathing. The relationship between VT and VI (Hey plot) (Hey, Lloyd, Cunningham, Jukes & Bolton, 1966) was employed as a method of quantifying any change in the relative contribution off and VT to overall VI. A plateau in VT was not reached during any of the subjects' CO2 rebreathing tests so that the VI: VT relationship could be described by a single linear regression equation. (B) The purpose of this experiment was to examine the time course of any changes in the ventilatory or breathing pattern response to CO2 following induction of inspiratory muscle fatigue. Six men, aged 23-35 years (mean, 31 years), volunteered for this experiment. CO2 rebreathing was performed in a fashion identical to experiment IIA. However, in this experiment, mouth occlusion pressures (Po.J (Whitelaw, Derenne & Milic-Emili, 1975) were measured every five to eight breaths during CO2 rebreathing. Po. was obtained in standard fashion using a commercial inflatable balloon system (Hans Rudolph 9300) attached to the inspiratory limb of the breathing circuit. In an attempt to reduce random variability, two CO2 response curves were obtained (separated by a 15 min rest period) at baseline and averaged. The subject rested for an additional 20 min following which he breathed through an inspiratory resistive load while maintaining 80% of the predetermined Pm, max in a fashion identical to experiment I and IIIA. Following the fatigue runs, the subject performed three Pm, max manoeuvres and the highest value was selected for comparison to baseline. CO2 rebreathing runs were then performed at 5, 10, 20, 40 and 60 min after the fatigue run.

0M. J. MADOR

20

AND

M. J.

TOBIN

Experiment IV In order to obtain additional evidence of the presence of fatigue following inspiratory resistive loading, we restudied three of the subjects that participated in experiment IIIB. During these experiments, gastric (Pga) and oesophageal (P.es) pressures were measured with balloon catheters. The subject's P,, max was recorded as in experiment II. The subject's 1oea max was recorded during a maximal Mueller manoeuvre. The subject then breathed through an inspiratory resistive load at in a fashion identical to that of the previous experiments (fatigue run). As in the 80 % of Poea previous experiments, when the subject could no longer reach the target pressure, all of the inspiratory muscles including the diaphragm were considered to be fatigued. Pdlmax and poes, max were recorded immediately following the fatigue run. During the fatigue run, the plateau of each square wave for P.,, and Pdi was measured breath-to-breath for 1 min at the beginning, during the middle and during the penultimate minute of the fatigue run. Duty cycle (71/TTOT) for the diaphragm and for the ribcage muscles was measured directly from the P,, and P.es tracings, respectively. We then calculated a tension-time index for the diaphragm ((Pdi/Pdimax) (n/TTOT)) (Bellemare & Grassino. 1982) and for the ribcage muscles ((PIes/poesmax) (71/TTOT)) (Fitting, Bradley. Easton, Lincoln. Goldman & Grassino. 1988). In addition, we examined the rate of relaxation during a voluntary sniff manoeuvre before and after the fatigue run. In these experiments, a sniff manoeuvre consisted of a short sharp inspiratory effort against an occluded airway while the subject wore a noseclip, as originally described by Esau, Bye & Pardy (1983). Subjects were educated in this technique during an initial trial period via a visual presentation of the sniff tracings. The criteria of Levy. Esau. Bye & Pardy (1984) were employed to determine whether a curve was acceptable for later analysis. Prior to performing the sniff manoeuvres, the response time of each balloon catheter-recorder system was measured by placing the balloon catheter in a pressurized larger balloon and bursting the latter with a hot needle to create a square-wave fall in pressure ('pop test'; Sykes, Vickers & Hull, 1981). The 10-90% rise time (tr) was found to be 0015 s. The maximum relaxation rate (MRR) was measured as the peak rate of pressure decay (dP/dtmax) during the sniff. Since the MRR is a function of the pressure generated during a sniff, it was normalized by dividing by AP (peak pressure -baseline pressure) to permit comparison of curves of different peak pressures (Esau et al. 1983). The time constant (r) of the later exponential phase of pressure decay (lower 70 % of curve) was also measured. The correlation coefficient of the individual exponential regression had to be greater than 0-98 for a measure of r to be accepted (Aubier, Murciano, Lecocguic, Viires & Pariente, max

1985)). Data analysis Differences in breathing pattern before and after resistive loading were analysed by two-tailed paired t tests (experiment I andII). The slopes of the ventilatory, mouth occlusion and breathing pattern responses to CO2 were calculated by least-squares linear regression. Differences in slope before and after resistive loading were compared by one-way analysis of variance with a repeatedmeasures design (experimentIII). If this overall comparison was significant. then the individual times following cessation of resistive loading were compared to the average of the two control trials. The MRR and T values were compared before and after resistive loading in each subject by unpaired t tests (experiment IN'). The Pax values were compared before and after resistive loading by paired t tests (experiment III and IN'). The results are expressed as the mean + standard error of mean unless otherwise stated. RESULTS

Experiment I

Metabolic and breathing pattern data at baseline and following the induction of fatigue are shown in Table 1. Immediately following removal of the resistive load, increased to 1670+1 98 compared with 651t+050 1 minm at baseline (P < 0-003). Importantly, the increase inVI was mediated solely by an increase in VT from 517+ 52 at baseline to 1192+ 211 ml (P < 0002), while there was no significant change infr, i.e. 1441 +1P8 vs. 15 4 +1P4 breaths min- (1P not significant). In order to determine if a very transient change in breathing pattern might have occurred, we =

BREA, THING PA TTERN AND }3A 1T' LU7E2

21

TABLE 1. Ventilatory and metabolic indices before and after the induction of inspiratory muscle fatigue Post-loading (fatigue state) Baseline (0t10 min) (0-2 min) (8-10 min) 12 (ml min 1\ 282 + 32 525+67*** 321 + 37* 234 + 28 543 + 61*** 257 + 26 c02 (ml min' ) 42 +0.1* 4-4+0-2 FET CO (%) 4-5+0-1 76+2 91+7* 80+6 fl (beats i-1) 6 51 + 050 16-70 + 1-98*** 1I (1 min') 7-66 + 0.54* 14 (mns) 5-17+52 565+66 1192+211*** 14-1 +1-8 15-4+ 1-4 14-5+1-3 fr (beats min-) Values are means+ S.E.M.. V - 7. T" O° uptake; VCO2, CO2 production; FET CO, end-tidal C02; f(. heart rate; P., minute Ventilation 14, tidal volume; and fr respiratory frequency. Statistical difference between baseline and fatigue state: *P < 0 05, **P < 001., ***P < 0 005. .2

TABLE 2. Breathing pattern before and after the induction of diaphragmatic fatigue Baseline Post-loading (fatigue state) (0-10 min) (4-9 min) 11(1 mmn1) 801+042 7-97+069 738+71 750+ 105 T" (ml) 10-9+ 1-5 10-7+1-9 fr (breaths min-') TI (s) 1-75+0-17 1-59+0-18 375+040 TE (S) 402+057 0 32+0-01 0 30+0 02 li/TTOT 043+003 047+004 14/IT (ml s-1) 4 9+0-2 5 0+0 3 FET C02 (0) Values are means+ .E.M.. n = 8. VI, minute ventilation; 1T. tidal volume; fr, respiratory frequency; TI inspiratory time; TE, expiratory time; li/TTOT' fractional inspiratory time; VT/E mean inspiratory flow; and FET 2' end-tidal CO2.

also examined the breathing pattern for the first 15 s following removal of the resistive load. During this time period VI was markedly elevated, i.e. 20 90+ 248 1 min-. This increase in VI was primarily achieved by an increase in VT from 517 + 52 to 1398 + 263 ml (P < 0 02); fr increased from 14-1 +1±8 to 17 4 + 2-8 breaths min- (P = not significant). At 8-10 min following removal of the fatiguing load, V1 was only mninimally elevated, i.e. 7-66 + 0-54 compared with 6 51 + 0 50 1 minat baseline (P < 0-05), and again rapid shallow breathing was not observed. In the period immediately following removal of the fatiguing load, V02 and Vc02 were increased compared with baseline, i.e. 525+67 vs. 282+32 ml min- (P < 0-003). and 543 +61 vs. 234+ 28 ml min-1 (P < 0-0003), respectively. However, endtidal CO2 (FET C0 ) was significantly decreased during this time period, i.e. 4-2 + 0 1 vs. 4 5 + 041 % (P < 0-05), indicating that the increase in VI was not solely due to the increase in 140 and that it represented true hyperventilation. Experiment II The breathing pattern at baseline and at 4-9 min following the induction of diaphragmatic fatigue is shown in Table 2. No differences in breathing pattern were observed between baseline and the fatigue state. In particular, rapid shallow

M. J. A4DOR AND A. J. TOBIN

22

breathing was not seen. Identical results were obtained when the first minute of baseline was compared to the first minute of breathing pattern measurements obtained after removal of the fatiguing load. In this experiment, we also measured the duty cycle (TI/TTOT) during the fatigue run in each subject. TI/ToT was 0-65+0-03. Since the subjects generated 60% of 60

-

40-i

E

-20-

0 J

5

6

8 7 FET CO2 (%)

9

10

Fig. 1. Ventilatory response to CO2 following induction of inspiratory muscle fatigue (0---0) compared with control measurements (0 O) in a representative subject. Following induction of fatigue, the slope of the ventilatory response to CO2 is significantly reduced in this subject (P < 0 05).

their Pdi max with each breath during the fatigue run, the diaphragmatic tension-time index exceeded 0 30 in all subjects. This is considerably above the fatigue threshold for the diaphragm of 0415-0-18 (Bellemare & Grassino, 1982).

Experiment lilA

Ventilatory response to CO2 In all subjects the ventilatory response to CO2 was linear with high correlation coefficients (mean 0-95 + 0-01); a representative example is shown in Fig. 1. Following induction of inspiratory muscle fatigue, the slope of the ventilatory response to CO2 was modestly reduced form 18-8 + 33 during control to 138 + 2-1 1 min-1 (FET CO %)-1 (P < 0 02). In the individual subjects, a reduction in the slope of the ventilatory response was observed in five of the six subjects (Fig. 2). In spite of the modest reduction in slope, VI at any given level of CO2 was not significantly altered by the induction of fatigue (Fig. 3). The VI at an FET o2of 7 % (the approximate FET co at the start of the CO2 rebreathing run) was slightly larger following induction of fatigue, i.e. 1526 + 560 1, compared with a control of 9-26 + 693 1, although this difference was not statistically significant.

VI: VT relationship The VI: VT relationship during CO2-stimulated breathing was linear with high correlation coefficients in all subjects (mean 0 94+0 01). Following induction of fatigue, the slope of the VI: VT relationship was reduced, i.e. 19-0 + 3 5, compared with

23

BR1EA THING PA TTERN AND FA TIG UE 6U

40

0

a)

ChC 7

a)0 X 20

Cu'

E

0

0. C)

Control

Fatigue

Fig. 2. Slope of ventilatory response to hypercapnia before and after the induction of inspiratory muscle fatigue in each subject (P < 0-02). Asterisk identifies subject shown in Fig. 1. 60

40 E

......

0

6

7

8

9

10

FET, CO2(%)

Fig. 3. Mean interpolated VI for FET CO values between 7 and 9 % following induction of fatigue (interrupted line) compared with control (continuous line). 95 % confidence limits for the VI values obtained following development of fatigue are represented by the finely stippled shading area, and the corresponding confidence limits for control values are represented by the diagonal notching. For any given FET C, the interpolated VI was not significantly altered by the development of fatigue.

27-0 + 4-7 minm during control (P < 0 03). None of the subjects displayed an increase in slope or leftward shift of the VI: VT curve following the development of fatigue, which would have indicated rapid shallow breathing.

Experiment IJIB

Ventilatory response to C02 In all subjects the ventilatory response to C02 was linear with high correlation coefficients (mean 0-95 + 0-01 ). The slope of the ventilatory response was significantly, albeit modestly, reduced following induction if inspiratory muscle fatigue compared with control (P < 0 025). Comparing sequential time periods following induction of 2

PHY 455

2M. J. MADOR AND M. J. TOBIN

24

fatigue with control, there was a significant reduction in slope at 10 and 20 min but not at 5, 40 or 60 min (Fig. 4). As in experiment IIIA, VI at any given level of CO2 was not significantly altered by the induction of fatigue. Again, VI at an FETT C2 of 7 % (the approximate F at the start of the CO2 rebreathing run) was slightly 25

C

0

-

U

0~

20

2_ 0

o

15-

C-

a)

>

10

, , Baseline

, 40 20 Time (min)

X

60

Fig. 4. Slope of the ventilator response to hypercapnia (mean +S.E.M.) before and at 5. 10, 20, 40 and 60 min following the induction of inspiratory muscle fatigue. Asterisk represents significant difference from control value (P < 0-05).

larger following induction of fatigue, i.e. 21V62 + 3 54 1 (at 5 min following induction of fatigue), compared with a control of 15'94 + 34 1, although this difference was not statistically significant. Breathing pattern response to C02 The VT CO2 and VI: VT relationships were linear in five of the six subjects. In one subject, the curves were linear and were excluded from analysis. The mean correlation coefficient for the VT CO2 relationship was 0(86 + 002 and for the VI: VT relationship it was 0-87 + 0-02. The fr: CO2 relationship was also examined. Four curves in three subjects were alinear. Fortuitously, all four alinear curves occurred at 20 and 60 min following induction of fatigue and these time periods were excluded from analysis of the fr:CO2 relationship. The mean correlation coefficient for the remaining fr: CO2 relationships was 0-85 + 0 02. Following induction of fatigue, there was no significant change in either the slope or the position of the VT CO2 curve. Also, there was no significant change in the position of the VI: VT relationship. However, as in experiment IIIA, a tendency for the slope of the ,I: VO relationship to decrease was observed following induction of fatigue compared with control (P = 0-054). There was no significant change in the position of the f: CO2 relationship following induction of fatigue. However, the slope of the fr:CO2 relationship was significantly reduced following induction of fatigue compared with control (I' = 0'03). The significant reduction in the slope of thefr: CO2 relationship was observed at 10 min but not at 5 or 40 min. Similar results were obtained when all curves in all subjects were included in the analysis. Clearly, as in experiment I1lA, there was no tendency towards rapid shallow breathing following induction of fatigue.

BREA THING PA TTERN AND F4 TIG L TE

25

15 0)

o

13

0

Qf

9

, . Baseline

. . , 20 40 Time (min)

60

Fig. 5. Mouth occlusion pressure (PI.O) at an end-tidal CO2 (FET Co2) of 9 % (mean+S.E.M.) before and at 5, 10, 20, 40 and 60 min following induction of inspiratory muscle fatigue. Asterisk represents significant difference from control value (P < 0 05). TABLE 3. Maximal pressure and tension-time indices

I-)~~~~~~~~~JPoes,

di. max

Subject no. 1

Baseline

Post-loading

174 265 201

127

Baseline 129

199

211

max

Post-loading

TTdi

92 181 157

0u23

TT,.c

0U35 0-33 3 164 178 0 39 Pdi max =maximal transdiaphragmatic pressure, P.,s max =maximal oesophageal pressure, TTdi = tension-time index of the diaphragm during loading, TTrc = tension-time index of the ribeage during loading. 2

0-24 0 28

Mouth occlusion pressure response to C02 The PoI1 CO2 relationship was generally linear (mean correlation coefficient, 0 88 + 001). Two curves following induction of fatigue were alinear and were excluded from analysis. The slope of the Po., response to CO2 following induction of fatigue was not significantly different from control. However, there was a shift in the position of the curve so that the Po., at any given level of CO2 was higher following induction of fatigue than during control (P < 001). A significant difference in the position of the Po.1 curve was observed at 10, 20 and 40 min, but not at 5 or 60 min following induction of fatigue (Fig. 5) compared with control.

I'm, max In all subjects, Pm, max fell following induction of fatigue from a baseline value of 148+17 to 118+16 cmH2O (P < 002). Experiment IV The tension-time index of the diaphragm (TTdJ) and for the ribeage (TTrc) is shown in Table 3. Pdi max was 214+28 cmH20 during control and fell to 163+21 cmH20 (P < 005) following induction of fatigue. P',eSmaX was 173+24cmH20 during control and fell to 143+27 cmH2O (P < 0 03) following induction of fatigue. Following induction of inspiratory muscle fatigue, a significant decrease in the 2-2

26

M. J. MADOR AND M. J. TOBNI

MRR for both diaphragmatic and oesophageal pressure was observed in each subject (Table 4). Similarly, following induction of fatigue, T was significantly increased for both diaphragmatic and oesophageal pressure in each subject. TABLE 4. Percentage change in relaxation parameters following induction of fatigue Subject Tdi () MRRoeS (/°) ARRdi () Toes no. +21 8 1 -145 +33-9 -65 2 -143 -14-6 +35-1 +30)0 + 35-3 3 - 13 0 -10-8 +47-9 MRRoes = maximum relaxation rate from the oesophageal pressure curve, MRRdi = maximum relaxation rate from the diaphragmatic pressure curve, Toes = exponential time constant from the oesophageal pressure curve, T(di = exponential time constant from the diaphragmatic pressure curve. DISCUSSION

The major findings in this study were: (1) inspiratory muscle fatigue did not cause rapid shallow breathing either during resting or C02-stimulated breathing, and (2) inspiratory muscle fatigue caused a reduction in the slope of the ventilatory response to CO2.

Critique of methods The question arises as to whether our subjects developed inspiratory muscle fatigue, since the study design did not always include an independent measure of fatigue. We employed the same method as Roussos and Macklem (Roussos & Macklem, 1977; Roussos et al. 1979) and others (Moxham, Wiles, Newham & Edwards, 1980; Moxham, Morris, Spiro, Edwards & Green, 1981; Jardim, Farkas, Prefaut, Thomas, Macklem & Roussos, 1981; Moxham, Edwards, Aubier, De Troyer, Farkas, Macklem & Roussos, 1982a; Moxham et al. 1982b; Esau et al. 1983; Levy et al. 1984; Aubier et al. 1985; Gallagher et al. 1985; Tobin, Perez, Guenther, Lodato & Dantzker, 1987) for the induction of inspiratory muscle fatigue. Extrapolating from the definition of skeletal muscle fatigue, i.e. the inability to maintain a predetermined load, Roussos and Macklem considered that the diaphragm was fatigued when the subject could no longer achieve a target Pdi by any means, and that all the inspiratory muscles were fatigued when the subject could no longer achieve a target Pm. The inability to generate the required pressure could be due to motivational factors, peripheral muscle contractile failure (peripheral fatigue) or a reduction in central neural motor drive (central fatigue). We made considerable efforts to exclude motivation as a factor by choosing only highly motivated subjects, and by constantly encouraging the subjects during the loaded breathing runs. Studies employing the same protocol and definition of fatigue but with measurement of diaphragmatic force generation in response to phrenic nerve stimulation have invariably shown the development of peripheral low frequency fatigue, as demonstrated by a reduction in force generation at the low physiological frequencies of stimulation (Aubier, Farkas, DeTroyer, Moses & Roussos, 1981; Moxham et al.

BREATHING PATTERN AND FATIGUE

27

1981, 1982a; Aubier et al. 1985; Bellemare & Bigland-Ritchie, 1987). Recently, Bellemare & Bigland-Ritchie (1987) have shown that a reduction in central motor drive (central fatigue) is an important factor leading to the inability to maintain a target pressure during loaded breathing. However, even in these experiments, peripheral fatigue was responsible for 50% of the force loss during loading. In our experiments, Pdi was set at 60 % and Pm at 80 % of maximum during loaded breathing, pressures that are well within the range capable of inducing fatigue. In order to obtain additional evidence of fatigue, we measured the TTdi in each subject in experiment II and it exceeded 0 30 in every subject. We also restudied three of the subjects from experiment 111B who were willing to swallow balloon catheters to allow measurement of PIes and Pdi (experiment IV). These subjects performed a loaded breathing run in a fashion identical to that of experiment I and III. The TTd was 0-25+0-02 and the fatigue threshold of 0'15-0-18 was exceeded in each subject (Bellemare & Grassino, 1982). The fatigue threshold for the ribcage has not been as clearly delineated. However, a TTrc of greater than 0-26 appears to be associated with fatigue of the ribeage muscles (Fitting et al. 1988). In our experiment, the TTrc was 0-36 + 0-02 and exceeded 0-26 in each subject. Thus, our method of inducing fatigue is capable of producing fatigue of both the ribcage muscles and the diaphragm. The fall in Pm max (experiment IIIB), Poes, max (experiment IV) and Pdi max (experiment IV) following loaded breathing provides further evidence that both the ribcage muscles and the diaphragm were fatigued. Finally, we calculated the maximum relaxation rate (MRR) and the time constant for relaxation (r) from both the Pdi and PoeJ curves (during brief voluntary inspiratory efforts) during the control period and following the loaded breathing runs. It is well known that as skeletal muscle fatigues, the relaxation rate slows (Edwards, Hill & Jones, 1972). The rate of relaxation can be assessed by measurement of the MRR and/or r. It has been shown that following induction of fatigue, the MRR (normalized for peak pressure) decreases while r increases (Esau et al. 1983; Levy et al. 1984). In experiment IV, we found that the MRR (normalized for peak pressure) was significantly decreased and -r significantly increased for both P.es and Pdi in every subject following the loaded breathing run, providing further evidence that peripheral fatigue of the inspiratory muscles occurred in our experiments. On the basis of the above points, we feel confident that peripheral fatigue of the inspiratory muscles was achieved in our subjects although a portion of the force loss during resistive loading could have been due to central fatigue. Pattern of breathing Roussos (1984) has postulated that somatic afferents from fatiguing respiratory muscles may impinge on the central controllers and cause alterations in respiratory timing resulting in rapid shallow breathing. In support of this view, rapid shallow breathing has been observed in the recovery period immediately following induction of diaphragmatic fatigue in both an anaesthetized dog (Road et al. 1987) and awake goat preparation (Oliven et al. 1988). To determine whether rapid shallow breathing occurs following the induction of inspiratory muscle fatigue in healthy conscious human subjects, we examined the breathing pattern in the recovery period immediately following removal of the fatiguing load. However, when post-load VI

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had returned to baseline levels, VT and fr values in the fatigue state were similar to those at baseline (Table and 2). This was the case regardless of whether fatigue was induced in all of the inspiratory muscles (experiment I) or just in the diaphragm (experiment II). On the basis of our prior work, we expected alterations in breathing pattern to become apparent when ventilation and, thus, respiratory work was increased. However, during C02-stimulated breathing, we again failed to detect rapid shallow breathing following the induction of fatigue, although peak VI during CO2 rebreathing was not that high (472 + 184 1 min-1 during the control trials). Furthermore, interpolated fr at an FET Co2 of 9 % (the average end-point for our CO2 rebreathing runs) tended to be higher following induction of fatigue, i.e. 21X3 + 6X8 breaths min- compared with a control of 18-3 + 4-6 breaths min-, although this difference did not reach statistical significance. In previous studies, we have examined the breathing pattern response during cycle exercise before and after the induction of inspiratory muscle fatigue (Mador & Acevedo, 1991 a,b). At the higher workloads ( 75% of V02 relative tachypnoea was clearly observed following induction of fatigue compared to control exercise. This finding indicates that inspiratory muscle fatigue in the presence of an enhanced inspiratory load can alter the pattern of breathing. However, in the present study, we have demonstrated that fatigue in the absence of an increased inspiratory load is not sufficient to produce rapid shallow breathing in healthy human subjects. Our results are in direct contrast with those of Gallagher et al. (1985) who observed rapid shallow breathing following the development of inspiratory muscle fatigue during unstimulated breathing in healthy subjects. However, a number of methodological differences exist between the two studies. Endurance times in our experiments were considerably longer (26+12 min) than in the study by Gallagher et al. (1985) (4+1 min). The difference in endurance times is primarily due to the different duty cycles (TI/TTOT) employed in the two studies: it was pre-set at0O60 in the study of Gallagher et al. (1985) whereas our subjects freely adopted a TI/TTOT which they could vary with each breath during loaded breathing. More importantly, Gallagher et al. (1985) recorded the breathing pattern in the period immediately following resistive loading and compared these measurements with control values VI was elevated following removal of obtained prior to the induction of fatigue. Since the resistive load, they obtained their control measurements duringCO2 rebreathing VI in the two instances. Such a comparison may not in order to ensure a comparable be valid since a number of investigators (Haldane, Meakins & Priestley, 1919; Gautier, 1969; Rebuck, Rigg & Saunders, 1976) have shown that the breathing pattern under non-steady-state conditions differs substantially depending on the stimulus employed to augment ventilation. These differences are particularly pronounced for the first few minutes following a sudden change in stimulus intensity (Gardner, Cunningham & Peterson, 1979), which is inevitable after the removal of a resistive load. To avoid this confounding effect, we used either the same stimulus (CO2 rebreathing) or no stimulus (resting breathing) to examine the breathing pattern during the control period and following the development of fatigue. Furthermore, in the period immediately following cessation of resistive loading, the breathing pattern may be influenced by a variety of metabolic, cardiac and behavioural factors induced by resistive loading per se. Cardiac output and both

Po

2

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increase during threshold loading at pressures equivalent to 50-60 % of Pm, max (Coast, Jensen, Cassidy, Ramanathan & Johnson, 1988). Similarly, body temperature and blood pressure increase during resistive loading in awake goats (Oliven et al. 1988). In addition, after cessation of a respiratory stimulus. there is often a transient hyperventilation due to neuronal after-discharge (Eldridge, 1974). This phenomenon has been best studied following voluntary hyperpnoea where the subsequent hyperventilation has been shown to be almost entirely due to an increase in VT with little change in fr (Swanson, Ward & Bellville, 1976; Folgering & Durlinger, 1983). If neuronal after-discharge is responsible for the transient hyperventilation observed following resistive loading it could negate the tachypnoeic influence of inspiratory muscle fatigue in the immediate recovery period. Thus, a variety of factors in addition to inspiratory muscle fatigue could influence the breathing pattern in the immediate recovery period. However, all these factors return quickly to control values following cessation of loading and would be unlikely to have significantly influenced our measurements taken later in the recovery period (Table 1, 8-10 min post-resistive loading, Table 2, and experiment III). Fatigue following inspiratory resistive loading usually consists of a high frequency and low frequency component (Edwards, 1979). High frequency fatigue recovers quickly and may not have been present at 5-10 min following cessation of loading. However, in subsequent fatiguing experiments, we have found that Pdi, max and Poes max were still significantly depressed at 15 min following cessation of loading suggesting that high frequency fatigue was still present at this time. Low frequency fatigue persists for several hours following its development and must have been present when our breathing pattern measurements were obtained. High rates of motoneurone discharge are rarely achieved in vivo except briefly during the initial stages of a vigourous contraction (Jones, Bigland-Ritchie & Edwards, 1979). Accordingly, low frequency fatigue is believed to be the more physiologically relevant form of fatigue.

Ventilatory response to C02 Following the induction of inspiratory muscle fatigue, the slope of the ventilatory response to hypercapnia was significantly decreased. The reduction in slope was seen at all times following induction of fatigue but only reached statistical significance at 10 and 20 min, possibly due to the relatively small number of subjects studied. A reduction in the slope of the ventilatory response to CO2 could represent a reduction in neural drive in response to C02, a decrease in muscle contractile force for a given neural input, or a combination of both factors. Moxham et al. (1982b) addressed this issue in three subjects using a similar protocol to induce inspiratory muscle fatigue as employed in our study; low frequency fatigue was verified by measurement of force generation in response to electrical stimulation. In their preliminary study, fatigue caused a reduction in the slope of the ventilatory response to CO2 but the surface diaphragmatic electromyogram increased, suggesting that the diminished response to CO2 was due at least in part to an impaired contractile response. Before attributing the reduction in CO2 responsiveness solely to fatigue, other possibilities must be considered. Breathing against an inspiratory resistive load

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involves considerable muscular exertion and some discomfort. The reduction in CO2 responsiveness may be a behavioural response to this exertion rather than to fatigue per se. The high intrathoracic pressures generated during inspiratory resistive loading may induce mild pulmonary congestion which by C fibre stimulation could alter CO2 responsiveness. However, C fibre stimulation would be expected to result in rapid shallow breathing and an enhanced ventilatory response (Coleridge & Coleridge, 1986), neither of which occurred in our study. Furthermore, Gallagher & Younes (1987) found no change in closing volume, a sensitive physiological index of pulmonary congestion, following inspiratory resistive loading to task failure (average peak inspiratory pressure -97 cmH20). Another factor that may have influenced subsequent CO2 responsiveness is the production of endogenous opiates during loading. Endorphins are released during inspiratory resistive loading and can modulate the respiratory response (Scardella, Parisi, Phair, Santiago & Edelman, 1986). However, despite a fourfold increase in blood endorphin levels, the ventilatory response to CO2 was not significantly altered following marathon running (Mahler, Cunningham, Skrinar, Kraemer & Colice, 1989). In our study, we measured Po.,, a crude index of respiratory drive (Whitelaw et al. 1975), and found that it was increased at any given level of CO2 following induction of fatigue compared with control. End-expiratory lung volume was not measured in this study. Thus, we cannot exclude the possibility that the increase in Po., was due to a systematic and persistent decrease in end-expiratory lung volume following induction of fatigue. However, Oliven et al. (1988) found that functional reserve capacity (FRC) measured immediately following cessation of loading was identical to control values suggesting that this is not likely to be an important factor in our study. The effect of fatigue on Po., measurements has not been fully delineated. However, fatigue would be expected either to reduce the Po., measured for a given neural input (Calverley, Laporta, Fleury, Comtois & Grassino, 1984) or to exert no effect (McDonough, Comtois, Hu & Grassino, 1988). Therefore, an increase in Po., following induction of fatigue indicates an increase in respiratory drive, albeit this increase may be underestimated. In spite of this increase in neural drive, the ventilatory response to CO2 remained depressed indicating that the contractile performance of the inspiratory muscles was impaired. However, subjects are capable of achieving much higher levels of ventilation during exercise following a similar fatigue protocol (Mador & Acevedo, 1991 a, b). This suggests that the inability to sufficiently increase inspiratory motor outflow to fully compensate for the diminished contractile performance of the inspiratory muscles may represent a form of central fatigue, similar to that observed in the awake goat (Oliven et al. 1988). In summary, we have shown that the induction of inspiratory muscle fatigue in healthy human subjects did not produce rapid shallow breathing either during resting or CO2-stimulated breathing. However, fatigue did cause a modest reduction in the slope of the ventilatory response to CO2. In conclusion, inspiratory muscle fatigue in the absence of a markedly enhanced inspiratory load is not sufficient to produce rapid shallow breathing in healthy human subjects. The authors thank Mr John Jankowski and Ms Susan M. Guenther for their technical assistance and Mrs Diane Poch for her preparation of the typescript. This work was supported in part by

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grants from the American Lung Association of New York, American Heart Association of New York and by VA Medical Research Funds.

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The effect of inspiratory muscle fatigue on breathing pattern and ventilatory response to CO2.

1. The effects of inducing inspiratory muscle fatigue on the subsequent breathing pattern were examined during resting unstimulated breathing and duri...
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