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ANESTH ANALG 809 1983;62809-14 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. 1983;62:8W-14 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 sighs. 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- I was measured at functional residual capacity (FRC). Measurements of vital capacity (VC) and forced ex- PARTIAL CURARIZATION AND BREATHING PATTERNS ANESTH ANALG 811 1983;62:809-14 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) 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) - -.. - - Control . 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. 1983,62:809-14 I2t l J 2\n,-&&4- 00 4w "I I CURARE 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- interval. 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) Normal 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 1983;62:809-14 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 References 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 ing may be related to proprioceptive responses from muscles during partial curarization in humans. J Appl Physiol 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- cle, but also affects the muscle within the muscle spin- ade on respiratory mechanics in conscious man. J Appl Physiol 1979;471162-8. dles (22). The ability of normal subjects to sense tidal 11. Gal TJ, Goldberg SK. Diaphragmatic function in healthy sub- volume with accuracy is in part dependent on the jects during partial curarization. J Appl Physiol 1980; 48:921- forces generated by the respiratory muscles (23). In- 6. 814 ANESTH ANALG ROSENBAUM ET AL. 1983;62:809-14 12. Gal TJ, Smith TC. Partial paralysis with d-tubocurarine and the 19. Siebens AA, Puletti F. Afferent units of dorsal roots driven by ventilatory response to CO,: an example of respiratory sparing? respiration. Science 1961;133:1418-9. Anesthesiology 1976;45:22-9. 20. Corda C, von Euler C, Lennerstrand G. Reflex and cerebellar 13. Askanazi J, Milic-Emili J, Broell JR, et al. Influence of exercise influences on a and on "rhythmic" and "tonic" y activity in and COz on breathing pattern of normal man. J Appl Physiol the intercostal muscle. J Physiol (London) 1966;184:898-923. 1979;47:192-6. 21. Campbell EJM, Friedman S, Clark TJH, et al. The effect of 14. Gal TJ, Arora NS. Respiratory mechanics in supine subjects muscular paralysis induced by tubocurarine on the duration during progressive partial curarization. J Appl Physiol1982;52:57- and sensation of breath-holding. Clin Sci Mol Med 1967;32425- 63. 32. 22. Molbech S, Johansen SH. Endurance time in static work during 15. Cohen EN. Blood brain barrier to d-tubocurarine. J Pharmacol Exp Ther 1963;141:356-62. partial curarization. J Appl Physiol 1969;27:44-8. 23. Woikove N, Altose MD, Kelsen SG, et al. Perception of changes 16. Foldes FF, Monte AP, Brunn HM, Wolfson B. Studies with in breathing in normal human subjects. J Appl Physiol1981;50:78- muscle relaxants in unanesthetized subjects. Anesthesiology 83. 1961;22:230-6. 24. Rigg JRA, Engel LA, Ritchie BC. The ventilatory response to 17. Smith SM, Brown HO, Torran JEP, Goodman LS. The lack of carbon dioxide during partial paralysis with tubocurarine. Br J cerebral effects of d-tubocurarine. Anesthesiology 1947;8:1-13. Anaesth 1970;42:105-8. 18. Critchlow V, von Euler C. Intercostal muscle spindle activity 25. Askanazi J, Silverberg PA, Hyman AI, et al. Patterns of ven- and its gamma motor control. J Physiol (London) 1963;168:820- tilation in postoperative and acutely ill patients. Crit Care Med 47. 1979;7:41-6.
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