ANESTH ANALG 809
Breathing Patterns during Curare-Induced Muscle Weakness
Stanley H. Rosenbaum, MD, Jeffrey Askanazi, MD, Allen I. Hyman, MD, and
John M. Kinney, MD
ROSENBAUM SH, ASKANAZI J, HYMAN Al, mUm2 and in inspiratory time from 1.51 to 1.71 sec (P <
KINNEY JM. Breathing patterns during curare-induced 0.05).Minute ventilation and inspiratorypow did not change.
muscle weakness. Anesth Analg 1983;62:809-14. However, when given 3% C02, both normal and partially
curarized subjects increased minute ventilation, from 2.3
This study examines the pattern of breathing used by normal to 5.7 Llminlm2 and from 2.5 to 6 . 7 Llminlm2, respectively.
subjects to compensate for an acute decrease in muscle The increases in both conditions were seconda y to increases
strength. A continuous infusion ofcurare was used to reduce in tidal volume. There was also a small increase in respi-
peak inspiratoy pressure in six normal subjectsfrom normal ratory frequency from 15.4 to 18 breathslmin, P < 0.01 in
control levels to - 45 cm H 2 0 (moderate weakness) and to the partially curarized group given 3% CO,. Because min-
-70 cm H 2 0 (mild weakness). Before administration of ute ventilation was preserved while vital capacity decreased,
curare, inspiratory pressure exceeded - 120 cm H 2 0 . A it is proposed that respiration is maintained in the presence
canopy-computer-spirometer system was used for nonin- of muscle weakness associated with curare by diaphragmatic
vasive spirometry and measurements of gas exchange. Par- function which remains relatively unaffected by curarization.
tial curarization to a mild level of muscle weakness did not
produce significant changes in the respiratory functions
studied. With a moderate level of muscle weakness, there Key Words: VENTILATION: d-tubocurarine, NEU-
were significant increases in tidal volume from 166 to 186 ROMUSCULAR RELAXANTS: d-tubocurarine.
The role of respiratory muscle weakness and fatigue sistance, which suggests that an optimal ratio of the
as a cause of respiratory failure has recently been two is sought. When breathing through an experi-
emphasized (1).The inspiratory pressure that can be mental fatiguing inspiratory resistance, normal sub-
sustained indefinitely without fatigue is related to the from
jects increase the inspiratory duty cycle, TIRTOT,
maximal attainable inspiratory pressure (2). Thus if a normal level of 0.4 to 0.8 (3). Under these circum-
muscle strength increases, the workload that can be stances, inspiratory flow decreases markedly.
sustained without fatigue will increase. Fatigue can The pattern of breathing used to compensate for
be precipitated by factors that increase muscle work muscle weakness has not been quantified nearly as
(resulting in an increase in inspiratory pressure) or well. Furthermore, the response to a CO, challenge
decrease in muscle strength (resulting in a decrease has not been well defined in the partially curarized
in maximum inspiratory pressure). The pattern of normal subject. This study examines the pattern of
breathing has been extensively examined in subjects breathing used by normal subjects in the supine po-
in whom respiratory muscle fatigue was induced by sition to compensate for an acute decrease in muscle
increasing muscle work due to imposition of a me- strength. A continuous infusion of d-tubocurarine
chanical load. There is a cycling of both inspiratory (curare) was used to reduce normal subjects’ peak
time (TI) and total breath time (TTOT)in normal sub- inspiratory pressure (PI max) from greater than - 120
jects who breathe through a fatiguing inspiratory re- to - 45 cm H20 (moderate weakness) and to - 70 cm
H20 (mild weakness) using a canopy-computer-
This study was supported by the National Institutes of Health spirometer system (3) to monitor breathing patterns.
Grants GM 14546, HL-23975, and U.S. Army Contract 49-193-MD- Additionally, responses to CO, in normal and par-
2552. tially curarized normal subjects were examined.
Received from the Departments of Anesthesiology, Medicine,
and Surgery, College of Physicians and Surgeons, Columbia-Pres-
byterian Medical Center, New York, New York. Accepted for pub-
lication March 24, 1983. Methods
Address correspondence to Dr. Rosenbaum, Department of
Anesthesiology, Columbia University College of Physicians and In the analysis of resting ventilation, six healthy sub-
Surgeons, 630 West 168th Street, New York, NY 10032. jects (non-obese, non-smokingmen), aged21-26 (mean,
0 1983 by the International Anesthesia Research Society
810 ANESTH ANALG ROSENBAUM ET AL.
23) years were studied. Mean body surface area was piratory volume in one second (FEVl.o)were made
1.89 m2 ? 0.08 m2 (sD). All subjects were within 10% with an Ohio spirometer. At least three baseline mea-
of their ideal body weight. Vital capacity (VC) and surements were made before the administration of
forced expiratory volume in 1 sec (FEV,,,) averaged curare and three more when the subjects were at a
4.2 L ? 0.5 L and 3.4 L t 0.5 L, respectively. All of steady state of muscle weakness. Figure 1shows sche-
them were accustomed to the canopy-spirometer sys- matically the protocol of curare administration for one
tem, as they had also been subjects for previous met- subject. All subjects had supplemental nasal oxygen
abolic or ventilation studies. When studied, the sub- and a free flowing intravenous infusion in place dur-
jects had been fasting for at least 8 hr. ing administration of curare. An experienced anes-
Our canopy-computer-spirometer system, de- thesiologist was present at all times.
scribed in detail previously (4), is composed of a 40- The first and second week after determining the
L head canopy connected to a spirometer (Med Sci- dose and rate of curare administration needed to
ence Model 470) and a Prime 300 computer. The can- produce the desired degree of muscle weakness, the
opy is a rigid transparent head chamber with a neck subject was brought back to the laboratory to repeat
seal, ventilated by a continuous 40 Limin airstream the same procedure but with the subject now in the
that passes to carbon dioxide (LIRA 200 FR) and ox- canopy-spirometer-computer system. Ten min were
ygen analyzers (Servomex OA 250). The spirometer allowed for equilibration after the subject was placed
is connected to the canopy and provides breath-by- in the canopy, and 15 min of baseline data were col-
breath measurement of changes in lung volume. This lected before the curare administration was begun.
system avoids the alterations in respiratory patterns Data then were collected during the 15-min period of
and ventilation caused by a face mask or by a mouth- steady state of muscle weakness at either the mild
piece with a nose clip (5). The spirometery and gas PI,,^ =
- 70 cm H20) or moderate (RmaX - 45 cm
exchange data are directly acquired and processed by H 2 0 ) level.
the computer. Air flow to the canopy is controlled to In the second phase of the study, the response to
provide a stable spirometer baseline position. Pro- a CO, challenge was examined in four normal sub-
grams are executed by the computer to quantify each jects. Each subject was studied at a moderate (-40
breath and to determine tidal volume (VT), respiratory
to -50 cm H20) level of muscle weakness produced
frequency (f), minute ventilation (VE),inspiratory time
in the manner previously described. During the pe-
(TI),total breath duration (TToT),inspiratory duty cycle
riod of weakness, the response to C 0 2 administered
(TI/TToT),and mean inspiratory flow (VT/TI).Inspi-
into the canopy was compared to data obtained dur-
ratory time is taken as the time from the onset of
ing a 5-min period breathing room air followed by
inspiration until the onset of expiration, and, hence,
administration of 3% COz. When a steady state was
includes the inspiratory plateau, if present (6). An
accuracy of t 10 ml in tidal volume measurements is achieved, another 5 min of data were collected on a
achieved for respiratory frequencies in the range of continuous basis. A paired Student’s t-test was uti-
5-40 breathsimin. The program excludes all volumes lized to analyze the data for determination of statis-
less than 50 ml because these are considered too small tical significance. This study was approved by the
to represent a breath. Tidal volumes greater than three Health Sciences Institutional Review Board of Colum-
times that subject’s mean tidal volume are considered bia University. The details of the study, including
On two occasions at least one week apart and at Figure 1. Schedule for administration of curare
least one week before the study, the subjects were
brought to our research unit and the dose of intra-
venous curare necessary to decrease (and maintain)
peak static inspiratory pressure PI,,^) at a mean - 45
cm H,O was established. PI,,, was measured every
30-60 sec using a Boehringer dynometer. All subjects
were studied at PI,,, = -45 cm H 2 0 (corresponding
to a moderate level of weakness), while only four
subjects were studied at PI,,, -70 cm H 2 0 (cor- v)
responding to a mild level of weakness). The PI,,, 5 -20-
was measured at functional residual capacity (FRC).
Measurements of vital capacity (VC) and forced ex-
PARTIAL CURARIZATION AND BREATHING PATTERNS ANESTH ANALG 811
Table 1. Percent Reduction (mean 2 SD) in Vital Capacity arized subjects were similar (Table 3). An increase in
(VC) and Forced Expiratory Volume in 1 sec (FEV,.,) at VT occurred in both and was the main reason for the
the Two Levels of Muscle Weakness increase in VE. Respiratory frequency increased sig-
PI,,, = -70 cm H,O PI,,, = -40 cm H20 nificantly in the partially curarized group (from 15.4
vc 14% t 5% 29% f 16% to 18.0 breathsemin-’, P < 0.01) but the increase was
FEV, n 14% f 4% 32% f 14% less than the increase in VT (165 ml/m2to 383 mum2,
Data are expressed as percent change from control levels before curari-
P < 0.01). Minute ventilation increased to a similar
zation. All studies were performed in the supine position. extent in both groups as did inspiratory flow. Inspi-
ratory time did not change significantly.
risks, were explained to all the subjects, and written
consent was obtained. Discussion
In this study we obtained the unexpected result of an
increased tidal volume and increased inspiratory time
Results during partial curarization (RmaX - 40 cm H20). In
Table 1 shows the decrease in VC and FEVl.oin the contrast to the pattern of breathing reported in this
subjects at each level of muscle weakness. VC and study, Newsom-Davis et a1.(6) reported a small tidal
FEVl.o measurements were obtained in only three of volume and rapid frequency in subjects with severe
the subjects at the mild level of weakness. respiratory weakness. Gibson et al. (7) also studied
Partial curarization to a mild level of muscle weak- patients with severe respiratory muscle weakness.
ness did not produce significant changes in the respi- Muscle weakness in the patients in the two studies
ratory functions studied (Table 2). When a greater was due to primary muscle disease (maltase defi-
level of muscle weakness was produced, there were ciency, limb girdle dystrophy, poliomyelitis, myas-
significant increases in VT from 166 to 186 mVm2 and thenic myopathy, Kugelberg-Welander syndrome).
in TI from 1.51 to 1.71 sec ( P < 0.05). A tendency for Breathing patterns of such patients consisted of an
the respiratory frequency to decrease appeared in 4 increased respiratory rate with a decreased tidal vol-
of 6 subjects, although this was not statistically sig- ume, results which are directly opposite to those re-
nificant. Minute ventilation did not change with cur- ported in this study with curare-induced muscle
arization, nor was there any change in mean inspi- weakness. Lung volume restriction in the study of
ratory flow ( V T ~ I )The mechanism for the increase Gibson et al. varied from 41% to 85% of predicted
in VT was the increase in TI, as inspiratory flow re- total lung capacity and from 20% to 59% of predicted
mained unchanged. There was very little apparent vital capacity. The reduction in vital capacity exceeds
effect of curarization on the tidal volume variability the reduction that occurred in this paper; thus the
as determined by inspection of the data in all of the patients in the study by Gibson had a greater degree
subjects. This is shown in a tidal volume histogram of muscle impairment. Additionally, their patients had
for two subjects in Figure 2. diseases of long duration. They concluded that an
Responses to 3% COz in normal and partially cur- unequal distribution of muscle weakness may have
Table 2. Changes in Respiratory Functions with Partial Curarization.
VT f VE WIT1
(mumz) (breathdmin) (L.ml-*.rnin) TI (sec) TTOT TIITTOT (ml.sec-’.rn2)
(Pimax= -40 cm H20)
Control 166 f 14 16.3 f 0.4 2.63 f 0.28 1.51 f 0.16 3.65 2 0.13 0.367 2 0.018 119 2 17
Curare 186 5 16 15.1 f 0.7 2.65 ? 0.33 1.71 f 0.16 4.05 f 0.29 0.374 f 0.015 114 * 14
P < 0.05 P < 0.05
(PlmaX 70 cm HzO)
- -.. - -
. 162 f 10 17.2 t 0.6 2.66 f 0.05 1.32 t 0.09 3.71 f 0.16 0.357 t 0.018 124 2 9
Curare 171 2 19 16.3 f 0.4 2.63 2 0.19 1.43 2 0.10 3.96 f 0.17 0.357 & 0.015 119 f 9
Abbreviations are defined in the text.
812 ANESTH ANALC ROSENBAUM ET AL.
Figure 2. Tidal volume histograms of two subjects in which tidal curarization in seated subjects (9) but is unaffected in
volume is plotted against percent of tidal volumes within a 20-ml those who remain supine (8). Specific airway con-
ductance is unaffected by partial curarization (10). Al-
though some asthmatic subjects do show an increase
contributed to changes in motion of the rib cage and in airway resistance in response to partial curariza-
abdomen during tidal breathing, maximum inspira- tion, none of the subjects included in the present
tion, and maximum expiration. Maximum inspiratory study had a history of asthma. Gal and Goldberg have
pressures were the least reduced, suggesting pres- demonstrated that even with a 42% decrease in max-
ervation of diaphragmatic strength. Because the dia- imum transdiaphragmatic pressure induced by partial
phragm is the prime generator of respiration at rest, curarization, there is only a minimal effect on quiet
this finding is consistent with our observation that breathing (11).
minute ventilation is preserved in partially curarized Because moderate curarization has been demon-
normal subjects. strated to have minor effects on the respiratory system
Lung compliance and elastic recoil of the lungs do in normal subjects, it could be suggested that the
not change in either supine (8) or seated (9) partially effects observed in this study, increased tidal volume
curarized subjects. However, the static PV curve of and increased inspiratory time with an unchanged
the lung is shifted in the sitting position (10) but not VE, are secondary to an alteration of lung function.
in the supine position during partial curarization (8). Gal and Smith (12) administered curare to six healthy,
Functional residual capacity is decreased by partial unanesthetized subjects and assessed the effects of
Table 3 . Breathing Patterns in Response to C 0 2 Inhalation In Normal and Partially Curarized Subjects
VT f VE TI VT/TI
(rnlim') (CPW (L,min '.m1k2) (set) (ml.m-z.sec- 1)
0% co, 151 t- 14 16.0 t 1.3 2.31 t- .25 1.71 2 .27 96 i 16
3% co, 331 t- 18" 17.7 2 1.2 5.68 t- .20' 1.45 .09 230 t- 8
0% co, 165 2 20 15.4 2 1.7 2.45 t- .43 1.62 2 .15 105 t- 16
37c CO? 383 2 37 18.0 t- 1.6 6.66 t .53" 1.64 t- ,170 236 2 19"
Taired t-test used to compare changes induced by 31, C 0 2with data obtained during room air breathing.
PARTIAL CURARIZATION AND BREATHING PATTERNS ANESTH ANALG 813
partial paralysis on breathing patterns and the re- creased tidal volume with partial curarization may
sponse to C02. Each subject received 0.2 mgikg over reflect change in the muscle spindle and hence a de-
a 40-min period, a dose comparable to that used in layed turn-off of inspiration. The responses- to co2
the present study. These investigators observed that breathing in normal and partially curarized subjects
there was no effect on VE during curare administra- were quite similar, VE increased to comparable levels.
tion. However, there was an increase in respiratory Furthermore, in both cases VT was the main reason
frequency and a reduction in VT from 1550 ml to 1050 for the increase in VE. This is consistent with the data
ml. The average control tidal volume of 1550 ml re- of Rigg et al. (24)who demonstrated that subjects with
ported by Gal and Smith is exceedingly high, far above a 34% decrease in vital capacity have no alteration in
the normal VT reported in healthy young adults unen- the response of minute ventilation to carbon dioxide.
cumbered by respiratory apparatus (13). Such an ini- In previous studies, we have demonstrated that
tially high VT could have been secondary to their use acutely ill patients breathe at a relatively fixed VT,
of invasive respiratory apparatus (5). Changes in the i.e., a narrow tidal volume distribution (25). This is
slope of the C 0 2 response curve in the subjects stud- similar to the phenomena observed in patients with
ied by Gal and Smith varied considerably but tended severe muscle weakness (7). We find no evidence in
to decrease. In the present study, the relation between the current study suggesting that this type of breath-
VE and inspired CO, was unchanged during partial ing pattern occurs in moderate muscle weakness alone
curarization. Furthermore, because VE was not sig- (Fig. 2). Thus rapid analysis of breathing patterns may
nificantly altered during the period of curare infusion, serve to distinguish alterations in ventilation due to
it would be unlikely that significant C 0 2 retention mild to moderate muscle weakness from those effects
occurred. If minute ventilation, metabolic CO, pro- due to severe muscle weakness and/or disease of the
duction, and pulmonary function all remain un- pulmonary parenchyma.
changed, then arterial Pco2should be unchanged also.
Gal and Arora (14) have demonstrated that flow
volume loops in partially paralyzed subjects exhibit a
pattern that suggests a variable extrathoracic obstruc-
tion to inspiration. This may reflect the adaptation of
the respiratory system to respiratory muscle weak- 1. Macklem PT, Roussos CS. Respiratory muscle fatigue: a cause
ness, or it may reflect actual upper airway obstruction of respiratory failure? Clin Sci Mol Med 1977;53:419-22.
in some of their subjects. We did not identify symp- 2. Roussos CS, Macklem PT. Diaphragmatic fatigue in man. J
Appl Physiol 1977;43:189-97.
toms of such obstruction in our subjects. However,
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geal obstruction (5). uous measurement of gas exchange and respiratory function.
J Appl Physiol 1972;33:523-8.
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