British Journal of Anaesthesia 1992; 68: 352-355
DOES A SUBPARALYSING DOSE OF VECURONIUM ENHANCE DIAPHRAGM FATIGUE? B. DUREUIL, C. LEBRAULT, J. BOCZKOWSKI, M. AUBIER AND P. DUVALDESTIN SUMMARY
KEY WORDS Neuromuscular relaxants: vecuronium, subparalysing dose. Ventilation: diaphragm fatigue.
A fraction of postsynaptic receptors of the neuromuscular junction may be occupied by a neuromuscular blocking agent without clinical sign of neuromuscular blocking effect, provided the fraction of receptors occupied is within the safety margin [1]. However, the safety margin varies according to the mode of nerve stimulation: the greater the frequency, the narrower is the safety margin [2]. During maximal contractions, there is an increase in the firing rate of motor neurones [3]. A small residual concentration of neuromuscular blocking drug may not affect muscle strength at rest, but may favour development of muscular fatigue. For respiratory muscles, Gal and Golberg observed that low doses of tubocurarine did not alter quiet breathing, but impaired maximal inspiratory capacity [4]. During recovery from anaesthesia, work of breathing may increase because of upper airway obstruction or shivering, and it is questionable if a residual concentration of blocker may hasten development of diaphragm fatigue. In order to test this hypothesis,
SUBJECTS AND METHODS
Assessment of diaphragm strength
We studied six healthy male volunteers, aged 25-45 yr, with the approval of our local Clinical Investigation Committee. All subjects were seated during the study. Diaphragm strength was assessed by measuring the transdiaphragm pressure (Pdi)—the difference between abdominal (Pga) and pleural pressure (Ppl). Pga and Ppl were measured using two balloon catheter systems connected by polyethylene tubing to the two ports of a differential pressure transducer (Validyne DP 15). One balloon, filled with 0.5 ml of air, was positioned in the middle one-third of the oesophagus [5] to measure changes in pleural pressure; the second, filled with 1 ml of air, was positioned in the stomach to determine changes in gastric pressure. Pdi was recorded during voluntary contractions produced by sniffing (PdiBnIfr) [6]. Subjects were instructed to make the sniff short and sharp, to achieve but not sustain peak Pdi,nirf, as indicated on an oscilloscope. The Pdianlff curve was analysed in two ways: peak Pdisnlff value was measured and considered an index of maximal diaphragm strength, and the time constant of diaphragm relaxation, T, was calculated from the later position of the Pdi decay curve [6] by plotting the pressure signal on a logarithmic scale [6]. This yielded a straight line over the 50-70 % lower part of the curve. The time constant T of this exponential position is equal to the reciprocal of the slope of this line [6]. Electrical muscle activity (EMG) of the diaphragm was recorded by an oesophageal electrode [7], from which the myoelectric potentials were passed to a Disa 15 G01 differential amplifier with band-pass filtering of 10-1000 Hz. The signal from the ampB. DUREUIL, M.D. (Department of Anaesthesia); M. AUBIKR, M.D.
(Department of Respiratory Physiology); Hdpital Bichat, Universiti Paris 7, 75018 Paris. C. LEBRAULT, MS)., Department of Anesthesia, Hopital Ambroise Pare, Universite Paris 5, 92104 Boulogne. J. BOCZKOWSKI, M.D., Clinique Pneumologique, INSERM Unite 226, Hfipital Beaujon, Universite Paris 7, 92110 Clichy. P. DUVALDESTIN, M.D., Department of Anesthesia, Hdpital Henri Mondor, Universite Paris 12, 94010 Creteil, France. Accepted for Publication: November 11, 1991. Correspondence to P.D.
Downloaded from http://bja.oxfordjournals.org/ at University of Manitoba on June 24, 2015
We have examined, in six healthy volunteers, the effect of a subparalysing dose of vecuronium on the development of diaphragm fatigue. Vecuronium was given as a 0.5-mg bolus i.v. followed by 0.5 mg infused over 30 min; as a control, saline was given in random order. Diaphragm strength was assessed by measuring transdiaphragm pressure and by electromyography. Diaphragm fatigue was induced by breathing against an inspirator/ resistance. The plasma concentration of vecuronium varied between 15 and30 ng ml~1 15 min after administration of vecuronium was started. Peripheral neuromuscular block was not detected in any subject. Diaphragm fatigue developed within the same period in both groups: mean 334 (SD 166) s after saline and 345 (190) s after vecuronium. The electromyographic pattern of diaphragm fatigue and the time constant of relaxation of transdiaphragm pressure after fatigue were similar in both groups. We conclude that, at low plasma concentrations of vecuronium, similar to those present in the postoperative period, there was no predisposition to diaphragm fatigue.
we have evaluated the effect of a low dose of vecuronium on diaphragm strength and endurance.
LOW-DOSE VECURONIUM AND DIAPHRAGM FATIGUE
353
Gastric pressure Pleural pressure Oesophageal electrode Inspiratory resistance Pneumotachograph
lifier was recorded simultaneously on a magnetic tape for further analysis. The signal from the tape was passed subsequently through two band-pass filters with ranges of 20-46 Hz for the lower frequency component (L) and 150-350 Hz for the high frequency component (H) [8]. The filtered signals were rectified and integrated and the results displayed on a paper recorder. Assessment of diaphragm endurance
For the diaphragm endurance test, subjects breathed through a Hans-Rudolf valve with the inspiratory inlet connected to a variable resistance. The inspiratory resistance was adjusted so that the subject could achieve a Pdi equal to 80% of the predetermined Pdi,niri. Pdi was displayed on an oscilloscope marked with the target pressure that the subject had to sustain for 2 s (fig. 1). Expiration was performed without added resistance. Ventilatory frequency was set at 12 b.p.m. and tidal volume at 0.75 litre. The endurance test was continued until the diaphragm fatigued, as defined by failure to sustain 80% Pdignirt for three or more consecutive breaths. Diaphragm EMG activity was recorded continuously throughout the endurance test. The amplitudes of the H and L signals were measured in arbitrary units, and the mean H: L ratio during three consecutive breaths was taken to give a single value for this time span. The H:L ratio was calculated at the 5th, 10th, 15th, 20th and 30th breaths of the endurance test. Monitoring of peripheral neuromuscular transmission
The ulnar nerve was stimulated at the wrist (Grass S 88) via surface electrodes, using train-offour stimuli delivered every 12 s throughout the study. The elicited strength of the adductor pollicis muscle was measured by a force displacement transducer (Statham UC3). The train-of-four ratio (T4:T1) was monitored continuously. Experimental procedure
After a period of 2 days of training, the subjects were studied on two days separated by 1 week.
Vecuronium or saline was given to each subject in a random order. Vecuronium 0.5 mg was given as a bolus, followed by a continuous infusion of vecuronium of 0.5 mg given over 30 min. To avoid diplopia after administration of vecuronium, subjects were blindfolded during the first 10 min. A venous blood sample (15 ml) was obtained from the antecubital vein of the contralateral arm before and 15 min after the start of the i.v. administration of vecuronium or saline, for measurement of plasma concentration of vecuronium in triplicate, in 2-ml samples using the Rose Bengale fluorimetric method [9]. The smallest detectable concentration of vecuronium was 10 ng ml"1 in a 2-ml plasma sample. A first set of Pdi^jur values was obtained 10 min after the start of administration of vecuronium or saline (tl), then diaphragm endurance was assessed. A second set of Pdi,nirt measurements was made within 15-30 s after the end of the endurance test (t2). Results are given as mean (SD). Comparisons between group data were evaluated by paired t test. The H:L ratio during the endurance test was compared using repeated measures analysis of variance. For all tests, P ^ 0.05 was considered significant. . RESULTS
No change in the elicited single twitch response or in T4:T1 ratio was observed throughout the study. Pdigout and T did not differ significantly after administration of vecuronium or saline (table I). Therefore, the target Pdi of the endurance test (80 % ^disnirr) was set at the same value for both groups. The duration of diaphragmatic endurance was 334 (166) s after saline and was virtually unchanged after vecuronium: 345 (190) s (fig. 2). After the endurance test, peak Pdi^^f was significantly smaller (P < 0.05), and T significantly greater (P < 0.05) than at tl after either vecuronium or saline, indicating that the diaphragm was fatigued in both groups. Pdignur and T did not differ significantly between the groups at t2. Because the individual variation in the daily H: L ratio derived from EMG measurements was large,
Downloaded from http://bja.oxfordjournals.org/ at University of Manitoba on June 24, 2015
FIG. 1. Experimental design. Subjects inspired through resistance to be able to produce a predetermined transdiaphragm pressure (Pdi). Pdi was measured with two balloons as the difference between gastric and oesophageal pressure (expressed as % of PdiTOlrT), and displayed on an oscilloscope, together with tidal volume. EMG of the diaphragm was measured by an oesophageal electrode.
BRITISH JOURNAL OF ANAESTHESIA
354 TABLB I. Mean values (SD) of transdiaphragm pressure during sniff test (Pdi^fff) and time constant of relaxation (T) before (tl) and after (tZ) diaphragm endurance test in the saline and vecuronium groups. Significant difference (P < 0.05) between tl and t2 values for all variables , (cm H,O)
tl t2
T
DISCUSSION
Saline
Vecuronium
Saline
Vecuronium
115(29) 96(30)
110(22) 95(25)
90(13) 102(17)
86(9) 96(11)
600 -
g £ 300
3 Q
i
600
FIG. 2. Individual (Q) and mean ( • (SD)) changes in endurance test duration after saline (S) and vecuronium (V) in the six subjects. Solid line = line of identity.
130 -
100 2 °E
70-
40-
10
30 25 15 20 Breath No. FIG. 3. Mean (SD) value of H: L ratio of diaphragm for all subjects as a function of breath number after saline ( • ) and vecuronium ( • ) . Each point is the average of three inspirations.
we averaged the H: L ratios of the first three breaths of each run, and assigned to the average a value of 100 %, using the method of Gross and colleagues [8]. The H : L ratios of the subsequent breaths were calculated as a percentage of this value. The mean changes in H: L ratio with time during the endurance test are shown in figure 3. There was a systematic decrease in H: L ratio after the first few breaths. No significant difference in the H : L ratio was noticed between saline and vecuronium throughout the endurance test.
The conditions produced in the present study are consistent with those usually found after spontaneous recovery from neuromuscular block. There was no sign of a neuromuscular blocking effect detectable by the usual methods of monitoring: there was no decrease in the elicited twitch response and no train-of-four fade, throughout the study. By comparing the changes in plasma concentration of vecuronium reported in other studies [10, 11] with our observations, we estimate that, after administration of vecuronium 0.1 mg kg"1, a plasma concentration of vecuronium ISngml" 1 is present within 90-200 min, and a concentration of 30 ng ml"1 within 70-150 min. In comparison, the spontaneous recovery to 100 % twitch tension has been shown to occur at 74 min after vecuronium 0.1 mg kg"1 [12]. Thus our study conditions approximately reproduced clinical conditions found up to 30 min after complete spontaneous recovery from vecuroniuminduced block. Several mechanisms may cause postoperative respiratory failure, including the residual depressant effect of anaesthetic agents on respiration, pulmonary regurgitation, pulmonary atelectasis, postoperative pneumothorax and respiratory muscle fatigue [13]. Diaphragm fatigue could be caused by impaired response of the muscle to excitation (contractile fatigue), by impaired neural or neuromuscular transmission (transmission fatigue), or both [3]. Diaphragm fatigue may occur more easily under circumstances when the muscle is weak, as during curarization. Gal and Golberg [4] demonstrated that administration of tubocurarine 0.15 mg kg"1 in normal subjects produced a 37 % decrease in maximum Pdi, which for a given work of breathing increases the ratio of Pdi to maximum Pdi, leading to earlier diaphragm fatigue [13]. However, diaphragm muscle impairment in this situation is associated with important clinical signs of peripheral block, inability to sustain a head lift for 5 s, and marked reduction of the train-of-four ratio of the adductor pollicis muscle in response to ulnar nerve stimulation. Because the dose of vecuronium we administered did not reduce maximal Pdi generation, it is unlikely that this agent favoured development of contractile fatigue. Although transmission fatigue has been questioned in normal man [3], failure of electrical neuromuscular transmission accompanies the loss of force that occurs during sustained maximal voluntary contraction of the adductor pollicis [14]. This phenomenon has been reported also in a rat model when diaphragm fatigue was induced by repeated phrenic nerve stimulation [15]; transmission fatigue contributes markedly to the fatigue induced by brief highfrequency stimulation, and prolongs that caused by low-frequency stimulation [3]. Neuromuscular blocking agents, even in small plasma concentrations,
Downloaded from http://bja.oxfordjournals.org/ at University of Manitoba on June 24, 2015
c
300 Duration (s): S
Vecuronium was detectable in the plasma of all subjects 15 min after the start of vecuronium administration in concentrations of 15 ng ml"1 (two subjects), 20 ng ml"1 (two) and 30 ng ml"1 (two).
LOW-DOSE VECURONIUM AND DIAPHRAGM FATIGUE
ACKNOWLEDGEMENT This study was supported by grants from CNAMTS, CRL 86.
REFERENCES 1. Paton WDM, Waud DR. The margin of safety of neuromuscular transmission. Journal of Physiology 1967; 191: 59-90. 2. Waud BE, Waud DR. The relation between the response to " train-of-four" stimulation and receptor occlusion during competitive neuromuscular block. Anesthesiology 1972; 37: 413-116. 3. Edwards RHT. Physiological analysis of skeletal muscle weakness and fatigue. Clinical Science and Molecular Medicine 1978; 54: 463-^170. 4. Gal TJ, Golberg SK. Diaphragmatic function in healthy subjects during partial curarization. Journal of Applied Physiology 1980; 48: 921-926.
5. Milic-Emili J, Mead J, Turner JM, Glauser EM. Improved technique for estimating pleural pressure from esophageal balloons. Journal of Applied Physiology 1964; 19: 207-221. 6. Levy RD, Esau SA, Bye PTB, Pardy RL. Relaxation rate of mouth pressure with snifis at rest and with inspiratory muscle fatigue. American Review of Respiratory Diseases 1984; 130: 38-41. 7. Grassino AE, Whitelaw WA, Milic-Emili J. Influence of lung volume and electrode position on the electomyography of the diaphragm. Journal of Applied Physiology 1976; 40: 971-975. 8. Gross D, Grassino A, Ross WRD, Macklem PT. Electromyogram pattern of diaphragmatic fatigue. Journal of Applied Physiology 1979; 46: 1-7. 9. Kersten DK, Ursula W, Meijer F, Agoston S. Fluorimetric and chromatographic determination of pancuronium bromide and its metabolites in biological materials. Climca Chimica Acta 1973; 44: 59-66. 10. Lynam DP, Caldwell J, Arden J, Miller RD, Cronnelly R, Castagnoli KP, Canfell C, Cannon JC. The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure. Anesthesiology 1988; 69: 227-231. 11. Arden JR, Lynam DP, Castagnoli KP, Canfell PC. Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology 1988; 68: 771776. 12. Chauvin M, Lebrault C, Duvaldestin P. The neuromuscular blocking effect of vecuronium on the human diaphragm. Anesthesia and Analgesia 1987; 66: 117-122. 13. Cohen CA, Zagelbaum G, Gross D, Roussos C, Macklem PT. r.liniral manifestations of respiratory muscle fatigue. American Journal of Medicine 1982; 73: 308-316. 14. Bellemare F, Garzaniti N. Failure of neuromuscular propagation during human maximal voluntary contraction. Journal of Applied Physiology 1988; 64: 1084-1093. 15. Aldrich TK, Shander A, Chaudhry I, Nagashima H. Fatigue of isolated rat diaphragm: role of impaired neuromuscular transmission. Journal of Applied Physiology 1986; 61: 1077-1083. 16. Waud BE, Waud DR. The margin of safety of neuromuscular transmission in the muscle of the diaphragm. Anesthesiology 1972; 37: 417-422. 17. Waud BE, Waud DR. The relation between tetanic fade and receptor occlusion in the presence of competitive neuromuscular block. Anesthesiology 1971; 35: 456-164. 18. DTiollander A, Duvaldestin P, Delcroix C, Nevelsteen M, Desmonts JM. Evolution of single twitch and train-of-four responses and of tetanic fade in relation to plasma concentrations of fazadinium in man. Anesthesia and Analgesia 1982; 61: 225-230.
Downloaded from http://bja.oxfordjournals.org/ at University of Manitoba on June 24, 2015
produce subclinical changes in neuromuscular transmission which may favour development of diaphragm fatigue. Although diaphragm muscle has a greater margin of safety than peripheral muscle [16], neuromuscular impairment may occur earlier when a sufficient number of receptors are blocked, while this muscle [15] is submitted to a high and sustained activation. Physiological muscle activation is tetanic, and tetanic fade corresponds to a lesser occupancy of postsynaptic receptors by non-depolarizing agents than does train-of-four fade [17, 18]. In our study, neither train-of-four ratio nor Pdi,^, was altered after administration of vecuronium. However, had sufficient diaphragm neuromuscular receptors been blocked by administration of a small dose of vecuronium, transmission fatigue may have been more likely to develop, especially with large values of Pdi [3]. Our finding that diaphragm fatigue developed similarly after administration of saline or vecuronium indicates that subclinical plasma concentrations of vecuronium do not impair diaphragm function or enhance diaphragm fatiguability.
355
DOES A SUBPARALYSING DOSE OF VECURONIUM ENHANCE DIAPHRAGM FATIGUE? B. DUREUIL, C. LEBRAULT, J. BOCZKOWSKI, M. AUBIER AND P. DUVALDESTIN SUMMARY
KEY WORDS Neuromuscular relaxants: vecuronium, subparalysing dose. Ventilation: diaphragm fatigue.
A fraction of postsynaptic receptors of the neuromuscular junction may be occupied by a neuromuscular blocking agent without clinical sign of neuromuscular blocking effect, provided the fraction of receptors occupied is within the safety margin [1]. However, the safety margin varies according to the mode of nerve stimulation: the greater the frequency, the narrower is the safety margin [2]. During maximal contractions, there is an increase in the firing rate of motor neurones [3]. A small residual concentration of neuromuscular blocking drug may not affect muscle strength at rest, but may favour development of muscular fatigue. For respiratory muscles, Gal and Golberg observed that low doses of tubocurarine did not alter quiet breathing, but impaired maximal inspiratory capacity [4]. During recovery from anaesthesia, work of breathing may increase because of upper airway obstruction or shivering, and it is questionable if a residual concentration of blocker may hasten development of diaphragm fatigue. In order to test this hypothesis,
SUBJECTS AND METHODS
Assessment of diaphragm strength
We studied six healthy male volunteers, aged 25-45 yr, with the approval of our local Clinical Investigation Committee. All subjects were seated during the study. Diaphragm strength was assessed by measuring the transdiaphragm pressure (Pdi)—the difference between abdominal (Pga) and pleural pressure (Ppl). Pga and Ppl were measured using two balloon catheter systems connected by polyethylene tubing to the two ports of a differential pressure transducer (Validyne DP 15). One balloon, filled with 0.5 ml of air, was positioned in the middle one-third of the oesophagus [5] to measure changes in pleural pressure; the second, filled with 1 ml of air, was positioned in the stomach to determine changes in gastric pressure. Pdi was recorded during voluntary contractions produced by sniffing (PdiBnIfr) [6]. Subjects were instructed to make the sniff short and sharp, to achieve but not sustain peak Pdi,nirf, as indicated on an oscilloscope. The Pdianlff curve was analysed in two ways: peak Pdisnlff value was measured and considered an index of maximal diaphragm strength, and the time constant of diaphragm relaxation, T, was calculated from the later position of the Pdi decay curve [6] by plotting the pressure signal on a logarithmic scale [6]. This yielded a straight line over the 50-70 % lower part of the curve. The time constant T of this exponential position is equal to the reciprocal of the slope of this line [6]. Electrical muscle activity (EMG) of the diaphragm was recorded by an oesophageal electrode [7], from which the myoelectric potentials were passed to a Disa 15 G01 differential amplifier with band-pass filtering of 10-1000 Hz. The signal from the ampB. DUREUIL, M.D. (Department of Anaesthesia); M. AUBIKR, M.D.
(Department of Respiratory Physiology); Hdpital Bichat, Universiti Paris 7, 75018 Paris. C. LEBRAULT, MS)., Department of Anesthesia, Hopital Ambroise Pare, Universite Paris 5, 92104 Boulogne. J. BOCZKOWSKI, M.D., Clinique Pneumologique, INSERM Unite 226, Hfipital Beaujon, Universite Paris 7, 92110 Clichy. P. DUVALDESTIN, M.D., Department of Anesthesia, Hdpital Henri Mondor, Universite Paris 12, 94010 Creteil, France. Accepted for Publication: November 11, 1991. Correspondence to P.D.
Downloaded from http://bja.oxfordjournals.org/ at University of Manitoba on June 24, 2015
We have examined, in six healthy volunteers, the effect of a subparalysing dose of vecuronium on the development of diaphragm fatigue. Vecuronium was given as a 0.5-mg bolus i.v. followed by 0.5 mg infused over 30 min; as a control, saline was given in random order. Diaphragm strength was assessed by measuring transdiaphragm pressure and by electromyography. Diaphragm fatigue was induced by breathing against an inspirator/ resistance. The plasma concentration of vecuronium varied between 15 and30 ng ml~1 15 min after administration of vecuronium was started. Peripheral neuromuscular block was not detected in any subject. Diaphragm fatigue developed within the same period in both groups: mean 334 (SD 166) s after saline and 345 (190) s after vecuronium. The electromyographic pattern of diaphragm fatigue and the time constant of relaxation of transdiaphragm pressure after fatigue were similar in both groups. We conclude that, at low plasma concentrations of vecuronium, similar to those present in the postoperative period, there was no predisposition to diaphragm fatigue.
we have evaluated the effect of a low dose of vecuronium on diaphragm strength and endurance.
LOW-DOSE VECURONIUM AND DIAPHRAGM FATIGUE
353
Gastric pressure Pleural pressure Oesophageal electrode Inspiratory resistance Pneumotachograph
lifier was recorded simultaneously on a magnetic tape for further analysis. The signal from the tape was passed subsequently through two band-pass filters with ranges of 20-46 Hz for the lower frequency component (L) and 150-350 Hz for the high frequency component (H) [8]. The filtered signals were rectified and integrated and the results displayed on a paper recorder. Assessment of diaphragm endurance
For the diaphragm endurance test, subjects breathed through a Hans-Rudolf valve with the inspiratory inlet connected to a variable resistance. The inspiratory resistance was adjusted so that the subject could achieve a Pdi equal to 80% of the predetermined Pdi,niri. Pdi was displayed on an oscilloscope marked with the target pressure that the subject had to sustain for 2 s (fig. 1). Expiration was performed without added resistance. Ventilatory frequency was set at 12 b.p.m. and tidal volume at 0.75 litre. The endurance test was continued until the diaphragm fatigued, as defined by failure to sustain 80% Pdignirt for three or more consecutive breaths. Diaphragm EMG activity was recorded continuously throughout the endurance test. The amplitudes of the H and L signals were measured in arbitrary units, and the mean H: L ratio during three consecutive breaths was taken to give a single value for this time span. The H:L ratio was calculated at the 5th, 10th, 15th, 20th and 30th breaths of the endurance test. Monitoring of peripheral neuromuscular transmission
The ulnar nerve was stimulated at the wrist (Grass S 88) via surface electrodes, using train-offour stimuli delivered every 12 s throughout the study. The elicited strength of the adductor pollicis muscle was measured by a force displacement transducer (Statham UC3). The train-of-four ratio (T4:T1) was monitored continuously. Experimental procedure
After a period of 2 days of training, the subjects were studied on two days separated by 1 week.
Vecuronium or saline was given to each subject in a random order. Vecuronium 0.5 mg was given as a bolus, followed by a continuous infusion of vecuronium of 0.5 mg given over 30 min. To avoid diplopia after administration of vecuronium, subjects were blindfolded during the first 10 min. A venous blood sample (15 ml) was obtained from the antecubital vein of the contralateral arm before and 15 min after the start of the i.v. administration of vecuronium or saline, for measurement of plasma concentration of vecuronium in triplicate, in 2-ml samples using the Rose Bengale fluorimetric method [9]. The smallest detectable concentration of vecuronium was 10 ng ml"1 in a 2-ml plasma sample. A first set of Pdi^jur values was obtained 10 min after the start of administration of vecuronium or saline (tl), then diaphragm endurance was assessed. A second set of Pdi,nirt measurements was made within 15-30 s after the end of the endurance test (t2). Results are given as mean (SD). Comparisons between group data were evaluated by paired t test. The H:L ratio during the endurance test was compared using repeated measures analysis of variance. For all tests, P ^ 0.05 was considered significant. . RESULTS
No change in the elicited single twitch response or in T4:T1 ratio was observed throughout the study. Pdigout and T did not differ significantly after administration of vecuronium or saline (table I). Therefore, the target Pdi of the endurance test (80 % ^disnirr) was set at the same value for both groups. The duration of diaphragmatic endurance was 334 (166) s after saline and was virtually unchanged after vecuronium: 345 (190) s (fig. 2). After the endurance test, peak Pdi^^f was significantly smaller (P < 0.05), and T significantly greater (P < 0.05) than at tl after either vecuronium or saline, indicating that the diaphragm was fatigued in both groups. Pdignur and T did not differ significantly between the groups at t2. Because the individual variation in the daily H: L ratio derived from EMG measurements was large,
Downloaded from http://bja.oxfordjournals.org/ at University of Manitoba on June 24, 2015
FIG. 1. Experimental design. Subjects inspired through resistance to be able to produce a predetermined transdiaphragm pressure (Pdi). Pdi was measured with two balloons as the difference between gastric and oesophageal pressure (expressed as % of PdiTOlrT), and displayed on an oscilloscope, together with tidal volume. EMG of the diaphragm was measured by an oesophageal electrode.
BRITISH JOURNAL OF ANAESTHESIA
354 TABLB I. Mean values (SD) of transdiaphragm pressure during sniff test (Pdi^fff) and time constant of relaxation (T) before (tl) and after (tZ) diaphragm endurance test in the saline and vecuronium groups. Significant difference (P < 0.05) between tl and t2 values for all variables , (cm H,O)
tl t2
T
DISCUSSION
Saline
Vecuronium
Saline
Vecuronium
115(29) 96(30)
110(22) 95(25)
90(13) 102(17)
86(9) 96(11)
600 -
g £ 300
3 Q
i
600
FIG. 2. Individual (Q) and mean ( • (SD)) changes in endurance test duration after saline (S) and vecuronium (V) in the six subjects. Solid line = line of identity.
130 -
100 2 °E
70-
40-
10
30 25 15 20 Breath No. FIG. 3. Mean (SD) value of H: L ratio of diaphragm for all subjects as a function of breath number after saline ( • ) and vecuronium ( • ) . Each point is the average of three inspirations.
we averaged the H: L ratios of the first three breaths of each run, and assigned to the average a value of 100 %, using the method of Gross and colleagues [8]. The H : L ratios of the subsequent breaths were calculated as a percentage of this value. The mean changes in H: L ratio with time during the endurance test are shown in figure 3. There was a systematic decrease in H: L ratio after the first few breaths. No significant difference in the H : L ratio was noticed between saline and vecuronium throughout the endurance test.
The conditions produced in the present study are consistent with those usually found after spontaneous recovery from neuromuscular block. There was no sign of a neuromuscular blocking effect detectable by the usual methods of monitoring: there was no decrease in the elicited twitch response and no train-of-four fade, throughout the study. By comparing the changes in plasma concentration of vecuronium reported in other studies [10, 11] with our observations, we estimate that, after administration of vecuronium 0.1 mg kg"1, a plasma concentration of vecuronium ISngml" 1 is present within 90-200 min, and a concentration of 30 ng ml"1 within 70-150 min. In comparison, the spontaneous recovery to 100 % twitch tension has been shown to occur at 74 min after vecuronium 0.1 mg kg"1 [12]. Thus our study conditions approximately reproduced clinical conditions found up to 30 min after complete spontaneous recovery from vecuroniuminduced block. Several mechanisms may cause postoperative respiratory failure, including the residual depressant effect of anaesthetic agents on respiration, pulmonary regurgitation, pulmonary atelectasis, postoperative pneumothorax and respiratory muscle fatigue [13]. Diaphragm fatigue could be caused by impaired response of the muscle to excitation (contractile fatigue), by impaired neural or neuromuscular transmission (transmission fatigue), or both [3]. Diaphragm fatigue may occur more easily under circumstances when the muscle is weak, as during curarization. Gal and Golberg [4] demonstrated that administration of tubocurarine 0.15 mg kg"1 in normal subjects produced a 37 % decrease in maximum Pdi, which for a given work of breathing increases the ratio of Pdi to maximum Pdi, leading to earlier diaphragm fatigue [13]. However, diaphragm muscle impairment in this situation is associated with important clinical signs of peripheral block, inability to sustain a head lift for 5 s, and marked reduction of the train-of-four ratio of the adductor pollicis muscle in response to ulnar nerve stimulation. Because the dose of vecuronium we administered did not reduce maximal Pdi generation, it is unlikely that this agent favoured development of contractile fatigue. Although transmission fatigue has been questioned in normal man [3], failure of electrical neuromuscular transmission accompanies the loss of force that occurs during sustained maximal voluntary contraction of the adductor pollicis [14]. This phenomenon has been reported also in a rat model when diaphragm fatigue was induced by repeated phrenic nerve stimulation [15]; transmission fatigue contributes markedly to the fatigue induced by brief highfrequency stimulation, and prolongs that caused by low-frequency stimulation [3]. Neuromuscular blocking agents, even in small plasma concentrations,
Downloaded from http://bja.oxfordjournals.org/ at University of Manitoba on June 24, 2015
c
300 Duration (s): S
Vecuronium was detectable in the plasma of all subjects 15 min after the start of vecuronium administration in concentrations of 15 ng ml"1 (two subjects), 20 ng ml"1 (two) and 30 ng ml"1 (two).
LOW-DOSE VECURONIUM AND DIAPHRAGM FATIGUE
ACKNOWLEDGEMENT This study was supported by grants from CNAMTS, CRL 86.
REFERENCES 1. Paton WDM, Waud DR. The margin of safety of neuromuscular transmission. Journal of Physiology 1967; 191: 59-90. 2. Waud BE, Waud DR. The relation between the response to " train-of-four" stimulation and receptor occlusion during competitive neuromuscular block. Anesthesiology 1972; 37: 413-116. 3. Edwards RHT. Physiological analysis of skeletal muscle weakness and fatigue. Clinical Science and Molecular Medicine 1978; 54: 463-^170. 4. Gal TJ, Golberg SK. Diaphragmatic function in healthy subjects during partial curarization. Journal of Applied Physiology 1980; 48: 921-926.
5. Milic-Emili J, Mead J, Turner JM, Glauser EM. Improved technique for estimating pleural pressure from esophageal balloons. Journal of Applied Physiology 1964; 19: 207-221. 6. Levy RD, Esau SA, Bye PTB, Pardy RL. Relaxation rate of mouth pressure with snifis at rest and with inspiratory muscle fatigue. American Review of Respiratory Diseases 1984; 130: 38-41. 7. Grassino AE, Whitelaw WA, Milic-Emili J. Influence of lung volume and electrode position on the electomyography of the diaphragm. Journal of Applied Physiology 1976; 40: 971-975. 8. Gross D, Grassino A, Ross WRD, Macklem PT. Electromyogram pattern of diaphragmatic fatigue. Journal of Applied Physiology 1979; 46: 1-7. 9. Kersten DK, Ursula W, Meijer F, Agoston S. Fluorimetric and chromatographic determination of pancuronium bromide and its metabolites in biological materials. Climca Chimica Acta 1973; 44: 59-66. 10. Lynam DP, Caldwell J, Arden J, Miller RD, Cronnelly R, Castagnoli KP, Canfell C, Cannon JC. The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure. Anesthesiology 1988; 69: 227-231. 11. Arden JR, Lynam DP, Castagnoli KP, Canfell PC. Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology 1988; 68: 771776. 12. Chauvin M, Lebrault C, Duvaldestin P. The neuromuscular blocking effect of vecuronium on the human diaphragm. Anesthesia and Analgesia 1987; 66: 117-122. 13. Cohen CA, Zagelbaum G, Gross D, Roussos C, Macklem PT. r.liniral manifestations of respiratory muscle fatigue. American Journal of Medicine 1982; 73: 308-316. 14. Bellemare F, Garzaniti N. Failure of neuromuscular propagation during human maximal voluntary contraction. Journal of Applied Physiology 1988; 64: 1084-1093. 15. Aldrich TK, Shander A, Chaudhry I, Nagashima H. Fatigue of isolated rat diaphragm: role of impaired neuromuscular transmission. Journal of Applied Physiology 1986; 61: 1077-1083. 16. Waud BE, Waud DR. The margin of safety of neuromuscular transmission in the muscle of the diaphragm. Anesthesiology 1972; 37: 417-422. 17. Waud BE, Waud DR. The relation between tetanic fade and receptor occlusion in the presence of competitive neuromuscular block. Anesthesiology 1971; 35: 456-164. 18. DTiollander A, Duvaldestin P, Delcroix C, Nevelsteen M, Desmonts JM. Evolution of single twitch and train-of-four responses and of tetanic fade in relation to plasma concentrations of fazadinium in man. Anesthesia and Analgesia 1982; 61: 225-230.
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produce subclinical changes in neuromuscular transmission which may favour development of diaphragm fatigue. Although diaphragm muscle has a greater margin of safety than peripheral muscle [16], neuromuscular impairment may occur earlier when a sufficient number of receptors are blocked, while this muscle [15] is submitted to a high and sustained activation. Physiological muscle activation is tetanic, and tetanic fade corresponds to a lesser occupancy of postsynaptic receptors by non-depolarizing agents than does train-of-four fade [17, 18]. In our study, neither train-of-four ratio nor Pdi,^, was altered after administration of vecuronium. However, had sufficient diaphragm neuromuscular receptors been blocked by administration of a small dose of vecuronium, transmission fatigue may have been more likely to develop, especially with large values of Pdi [3]. Our finding that diaphragm fatigue developed similarly after administration of saline or vecuronium indicates that subclinical plasma concentrations of vecuronium do not impair diaphragm function or enhance diaphragm fatiguability.
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