Breathing Patterns during Curare Induced Muscle Weakness

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					                                                                                                            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)    (*.rnin)         TI (sec)      TTOT          TIITTOT     (ml.sec-’.rn2)
                                                                  Moderate weakness
(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
                                                                      Mild weakness
(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.

                    I2t    l

                    00     4w



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
Partially curarized
  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,
in the subjects studied by Gal and Arora, ventilatory       3. Grassino A, Bellemare F. Respiratory muscle fatigue and its
                                                               effect on breathing pattern. In: von Euler C, Lagercrantz H,
measurements were made with a mouthpiece in place.             eds. Central nerve control mechanism in breathing. New York:
It is possible that in the partially paralyzed subject         Pergamon, 1979:465.
the mouthpiece itself may contribute to oropharyn-          4. Spencer JL, Zikria BA, Kinney JM, et al. A system for contin-
geal obstruction (5).                                          uous measurement of gas exchange and respiratory function.
                                                               J Appl Physiol 1972;33:523-8.
    Curare is not thought to alter central nervous sys-
                                                            5. Askanazi J, Silverberg PA, Foster RJ, et al. Effect of respiratory
tem function, therefore one cannot postulate a neu-            apparatus on breathing pattern. J Appl Physiol1980;48:577-80.
rogenic mechanism for our present results (15-17).
                                                            6. Newsom-Davis J, Stagg D, Loh L, Casson M. The effect of
The respiratory muscles are abundantly supplied with           respiratory muscle weakness on some features of the breathing
muscle spindles (18,19), some of which have a tonic,           pattern. Clin Sci Mol Med 1976;50:10P-llP.
not a rhythmic, activity (20). Campbell et al. (21)found    7. Gibson GJ, Pride NB, Newsom-Davis J, Loh LC. Pulmonary
that in conscious subjects fully paralyzed by curare,          mechanics in patients with respiratory muscle weakness. Am
                                                               Rev Respir Dis 1977;115:389-95.
the distressing sensation caused by prolonged breath
holding at resting lung volume is absent. This was         8. Gal TJ, Goldberg SK. Relationship between respiratory muscle
                                                              strength and vital capacity during partial curarization in awake
true at arterial Pco2 levels that ranged from 50 to 60        subjects. Anesthesiology 1981;54:141-7.
mm Hg and suggests that the distress of breath hold-       9. DeTroyer A, Bastenier J, Delhez L. Function of respiratory
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the skeletal muscle of the chest wall. Curare not only        1980;49:1049-56.
blocks neuromuscular transmission in skeletal mus-         10. Detroyer A, Bastenier-Geens J. Effects of neuromuscular block-
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dles (22). The ability of normal subjects to sense tidal
                                                           11. Gal TJ, Goldberg SK. Diaphragmatic function in healthy sub-
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forces generated by the respiratory muscles (23). In-          6.
814         ANESTH ANALG                                                                                                 ROSENBAUM ET AL.

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