An independent investigator, blinded to the treatment and any other experimental condition, observed the video recordings at the end of each study day and decided a movement/no movement response. Any type of visible movement of the isolated arm was characterized as such. Based on the movement/no movement response for each particular treatment, we adjusted the EtDes concentration for the respective treatments in the next volunteer.
Median effective EtDes for immobility (EtDes50 or MACtetanus) estimates were calculated based on Dixon’s approach, which takes the average of the concentrations in the sample as the estimated MACtetanus.19 Bootstrap resampling20 was used to determine confidence intervals for the MACtetanus estimates. One hundred thousand bootstrap samples (simple random samples of size 24 with replacement, retaining the original order of the volunteers in the study) were simulated from the observed data. The first volunteer in each bootstrap sample was thus removed, and 1 observation was added to the end of each bootstrap sample by inferring from the EtDes concentration/response combination for the last observation in the original bootstrap sample what the EtDes concentration would have been.
The bootstrap sampling distributions were used for inferences on MACtetanus for the 3 treatments (saline, succinylcholine, or mivacurium), as well as inferences on the differences in MACtetanus among the 3 treatments. Confidence limits for the sample MACtetanus were taken as the 2.5th and 97.5th quantiles from these distributions. Tests of the difference in MACtetanus among the treatments used a z-statistic calculated as a ratio of the mean difference and the standard deviation of the bootstrap distribution for the difference. The experiment-wide significance level was controlled at 0.05 by implementing Bonferroni adjustment for multiple comparisons.
Nonlinear mixed-effects modeling (NONMEM VI, GloboMax LLC, Hanover, MD) was used to evaluate the effect of mivacurium and succinylcholine on the relationship between BIS and EMGBIS, before, as well as after, the noxious stimulation, using the nested models approach. Graphs showing the change in BIS and EMGBIS as a function of EtDes, as well as the relationship between BIS and EMGBIS, were used to visually explore associations between these model parameters. The effect of different treatments on the EtDes concentration versus BIS relationship before the occurrence of the noxious stimulation was modeled separately. In the final (full) model, all experimental data were included. During each modeling process, any added parameter was considered significant (χ2 < 0.05) if it produced a reduction of at least 3.84 points in the −2 log likelihood of the model. A detailed description of the NONMEM modeling process for BIS response is provided in the Appendix (see Supplemental Digital Content 1, http://links.lww.com/AA/A12).
The maximum values of SBP and HR during a 1-min-long period of continuous recording immediately before and after drug administration, as well as after the application of noxious stimulation, were used in the analysis of hemodynamic response. Based on the Kolmogorov-Smirnov test (α level set at 0.05), these data did not follow a normal distribution. Consequently, Wilcoxon’s signed rank test was used to compare SBP and HR values between same and different phases of the experiment across the 3 drug treatments. Twelve paired comparisons among the different phases of the experiment were performed, which adjusted the α level to 0.05/12 = 0.0041.
Hemodynamic responses, EtDes concentration, BIS, and EMGBIS at baseline (before drug administration) were compared across the different treatments, using Friedman test (nonparametric data) or repeated-measures analysis of variance and then appropriate post hoc tests. Data are presented as median (interquartile range) or mean ± sd, and an α level of 0.05 was used to denote statistical significance.
One volunteer did not complete the study because of gastric fluid regurgitation during inhaled induction of anesthesia. However, his immediate recovery was uneventful. Twenty-four consecutive subjects (9 women) completed the study. They were 27 ± 6 years old, weighed 75 ± 12 kg, and were 174 ± 7 cm tall.
Before study drug administration, hemodynamic and respiratory variables were similar among the different treatments. Volunteers remained normothermic during all phases of the experiment. By study design (up-and-down method), succinylcholine and mivacurium treatments were associated with lower EtDes concentrations and, as a result, with higher BIS values (Table 1).
During all NMB treatments, a reliable NMB and an intact TOF response were detected in the perfused and isolated arms, respectively. Both responses were obtained immediately after the end of the observation (video recording) period and before releasing the tourniquet.
Figure 2 shows the crossover EtDes concentrations for the different treatments. Table 2 presents the EtDes50 estimates for immobility (MACtetanus). Saline treatment was associated with a MACtetanus (95% confidence interval) of 5.00% (4.85–5.13). The administration of succinylcholine and mivacurium significantly reduced that value to 4.05% (3.81–4.29) and 3.84% (3.60–4.08), respectively. The difference in MACtetanus between succinylcholine and mivacurium was not statistically significant.
A detailed report regarding the NONMEM model and the various parameters that determined the BIS response is provided in the Appendix (see Supplemental Digital Content 1, http://links.lww.com/AA/A12). According to the model, both the EMGBIS and the EtDes concentration had a significant effect on BIS response. Noxious stimulation increased BIS during all treatments (i.e., saline, succinylcholine, and mivacurium), independently of an increase in the EMGBIS activity.
Before the occurrence of noxious stimulation, only succinylcholine had a small (approximately 1 U increase) but significant effect on BIS, which was independent of EMGBIS activity. After the onset of the noxious stimulation, both saline and succinylcholine treatments were associated with an additional significant increase in BIS response of approximately 1 U, for which the inclusion of the EMGBIS and noxious stimulation effects into the model could not fully account.
During saline, SBP increased from a median (interquartile range) of 101 (96–109) mm Hg before the noxious stimulation to 125 (102–164) mm Hg after the noxious stimulation (P < 0.001), whereas HR increased from 71 (66–76) bpm to 88 (71–115) bpm (P < 0.001). Succinylcholine administration was associated with a significant increase in SBP from 98 (94–107) mm Hg to 124 (114–153) mm Hg (P < 0.0001), whereas HR increased from 70 (60–75) bpm to 90 (74–112) bpm (P < 0.001). The noxious stimulation did not further increase SBP and HR, which remained significantly higher compared with baseline. During mivacurium, SBP and HR did not change significantly between the pre- and poststimulation period.
None of the volunteers reported awareness of any event during anesthesia.
This is the first study to characterize the effect of NMB on the volatile anesthetic requirements for immobility and cortical anesthetic end points in humans using a potent noxious stimulus. We found that both succinylcholine and mivacurium reduce the anesthetic demand for immobility and they are associated with similar BIS activation patterns in response to noxious stimulation compared with saline treatment.
By using the isolated forearm technique, we found that succinylcholine and mivacurium reduced MACtetanus for desflurane by 19% and 23%, respectively. Our study confirms previous findings by Forbes et al.,5 who showed that pancuronium reduced halothane MACincision by 25%. In contrast, Fahey et al.21 did not manage to show any difference in halothane MACincision among nonparalyzed patients and patients treated with atracurium, vecuronium, or pancuronium. However, the different numbers of isolated extremities, as well as the different starting halothane concentrations in the different patient groups, might raise a concern regarding the accuracy of those MAC estimates.22
Saline treatment was associated with a MACtetanus of 5.0 vol%, which approximates those previously estimated by Greif et al.14 (4.9 ± 0.7 vol%) and Jones et al.17 (4.58 ± 0.6 vol%), using a similar study design but without using the isolated forearm technique. This supports not only the successful isolation of the tested limb in our experiment but also the complete recovery of neuromuscular function in between the administration of the different drug treatments. To provoke movement, we applied tetanic electrical stimulation. As we23 and others24,25 have previously shown, our MACtetanus values were lower than those produced by skin incision in surgical patients (MACincision).
Muscle relaxants do not readily cross the blood-brain barrier26 and therefore do not exert a direct effect on the CNS; an indirect action via an active metabolite of succinylcholine or mivacurium is also unlikely. Hemodynamic stability during and immediately after the administration of mivacurium suggests that little, if any, histamine was released. Furthermore, animal evidence indicates that neuronal histamine release reduces, rather than increases, the MAC of halothane.27 Our findings are thus consistent with the afferentation theory, which proposes that loss of tonic afferent input to the CNS would suppress its activity, resulting in decreased anesthetic requirements.
BIS quantifies the relationship among the underlying sinusoidal components of the EEG28 and is proposed as a surrogate measure of the hypnotic (cortical) component of IV,29 as well as volatile,2,30 anesthetics. Perioperative noxious stimuli alter brain electrical activity31–35 and result in a rightward shift of the BIS versus EtDes concentration response curve,36 whereas 1-MAC anesthesia is not sufficient to suppress BIS,10,11 or auditory-evoked37 potentials, in response to surgical incision. Evidence supports that the magnitude and pattern of this EEG response relate to the underlying anesthetic depth32,33 and are independent of the presence of NMB when stimulation occurs at deeper, rather than lighter, levels of anesthesia.35,38 Our data support these findings; noxious stimulation significantly increased BIS, and this response was independent of muscle relaxation or an EMGBIS effect. Conversely, the effect of succinylcholine on BIS in the pre- and poststimulation period was independent of EMGBIS, whereas noxious stimulation completely accounted for the small increase in BIS during mivacurium treatment. Saline treatment was associated with a high EMGBIS, whereas the latter was almost completely suppressed during the muscle relaxation treatments.
Although increased frontal EMG can distort the BIS calculation via altering its Beta Ratio frequency (30–47 Hz) component,28 it might also reflect a “true” EEG component in the higher frequency range (γ band) because stand-alone EMG using submental,39 as well as temporofrontal,35 recordings have demonstrated a negligible contribution of the facial EMG signal on EEG during anesthesia. The possibility that this high-frequency “EMG” activity could signify conscious processing of information40 during anesthesia is undetermined. Desflurane concentrations just above MACawake are sufficient to suppress recall of information acquired during anesthesia in nonstimulated subjects41; nevertheless, the effect of a noxious arousing stimulus on this process remains to be investigated. Evidence suggests that implicit learning during anesthesia varies as a function of both the hypnotic depth42 and analgesic state.43
Succinylcholine administration increased BIS before and after the application of noxious stimulation. This small but significant effect was independent of EMGBIS activation, and the presence of a “true” EEG component cannot be excluded. These data are in accordance with previous reports supporting the afferentation theory by demonstrating the hyper-afferentative properties of succinylcholine.6,7,44 Succinylcholine- and noxious stimulation-induced EEG activations are not synonymous with conscious awareness, which, according to the theory of neuronal adequacy, previously proposed by Libet et al.,45 would require certain temporal, as well as spatial, neuronal assembly requirements to develop.46
Considerable animal9 and human11 evidence suggests that various inhaled9,11 and IV47 anesthetics prevent movement via a direct action on the spinal cord. However, an indirect MAC-sparing3 and hypnotic-sparing2 effect of epidural anesthesia in humans, as well as the depressed excitability of reticulo-thalamo-cortical arousal mechanisms in an animal model of neuraxial anesthesia,48 reflect an existing interaction between cortical and subcortical levels of the nervous system. Although an effect of NMB on both cortical and subcortical levels of the CNS is a possibility, the administration of a potent noxious stimulation led to a pharmacological separation of the structures governing immobility and cortical anesthetic end points.
Noxious stimulation during near-MAC desflurane was followed by a significant increase in cardiovascular activities. Interestingly, mivacurium suppressed the associated autonomic responses. This effect of mivacurium is in agreement with its effect on immobility and supports the view that cardiovascular responses to noxious stimuli during anesthesia are mainly governed by spinal and supraspinal CNS sites.49 These results are in contrast with the findings by Gibbs et al.,50 who showed that vecuronium administration in rats during infra-MAC anesthesia did not alter hemodynamic response to noxious stimulation.
In conclusion, both succinylcholine and mivacurium reduce the desflurane requirement for immobility during near-MACincision anesthesia, without affecting cortical activation in response to a potent noxious stimulation. Succinylcholine administration is associated with an arousal response, as determined by BIS. Importantly, whereas cardiovascular reaction to a noxious event is ablated by mivacurium, cortical response is retained. The anesthetic requirement might thus be underestimated if based only on signs of autonomic function.
The authors appreciate the contributions of Marina Varbanova, MD, Ching-Rong Cheng, MD, Dorothea Rosenberger, MD, Jay King, BS (medical student), Teresa V. Joiner, RN, CRC, and Annette Robinson, RN, BSN, all from the Department of Anesthesiology and Outcomes Research Institute at the University of Louisville. The authors thank Joseph F. Antognini, MD, for his input, and Lawrence Saidman, MD, for his constructive critique of the manuscript.
1.Lanier WL, Iaizzo PA, Milde JH, Sharbrough FW. The cerebral and systemic effects of movement in response to a noxious stimulus in lightly anesthetized dogs. Possible modulation of cerebral function by muscle afferents. Anesthesiology 1994;80:392–401
2.Hodgson PS, Liu SS. Epidural lidocaine decreases sevoflurane requirement for adequate depth of anesthesia as measured by the Bispectral Index monitor. Anesthesiology 2001;94:799–803
3.Hodgson PS, Liu SS, Gras TW. Does epidural anesthesia have general anesthetic effects? A prospective, randomized, double-blind, placebo-controlled trial. Anesthesiology 1999;91:1687–92
4.Hodes R. Electrocortical synchronization resulting from reduced proprioceptive drive caused by neuromuscular blocking agents. Electroencephalogr Clin Neurophysiol 1962;14:220–32
5.Forbes AR, Cohen NH, Eger EI II. Pancuronium reduces halothane requirement in man. Anesth Analg 1979;58:497–9
6.Lanier WL, Milde JH, Michenfelder JD. Cerebral stimulation following succinylcholine in dogs. Anesthesiology 1986;64:551–9
7.Oshima E, Shingu K, Mori K. E.E.G. activity during halothane anaesthesia in man. Br J Anaesth 1981;53:65–72
8.Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C, Wierda JM. Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics. Anesthesiology 2007;106:935–43
9.Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 1993;79:1244–9
10.Sandin M, Thorn SE, Dahlqvist A, Wattwil L, Axelsson K, Wattwil M. Effects of pain stimulation on bispectral index, heart rate and blood pressure at different minimal alveolar concentration values of sevoflurane. Acta Anaesthesiol Scand 2008;52:420–6
11.Rehberg B, Bouillon T, Gruenewald M, Schneider J, Baars J, Urban BW, Kox WJ. Comparison of the concentration-dependent effect of sevoflurane on the spinal H-reflex and the EEG in humans. Acta Anaesthesiol Scand 2004;48:569–76
12.Liu N, Chazot T, Huybrechts I, Law-Koune JD, Barvais L, Fischler M. The influence of a muscle relaxant bolus on bispectral and datex-ohmeda entropy values during propofol-remifentanil induced loss of consciousness. Anesth Analg 2005;101:1713–18
13.Greif R, Greenwald S, Schweitzer E, Laciny S, Rajek A, Caldwell JE, Sessler DI. Muscle relaxation does not alter hypnotic level during propofol anesthesia. Anesth Analg 2002;94:604–8
14.Greif R, Laciny S, Mokhtarani M, Doufas AG, Bakhshandeh M, Dorfer L, Sessler DI. Transcutaneous electrical stimulation of an auricular acupuncture point decreases anesthetic requirement. Anesthesiology 2002;96:306–12
15.Morioka N, Akca O, Doufas AG, Chernyak G, Sessler DI. Electro-acupuncture at the Zusanli, Yanglingquan, and Kunlun points does not reduce anesthetic requirement. Anesth Analg 2002;95:98–102
16.Chernyak G, Sengupta P, Lenhardt R, Liem E, Doufas AG, Sessler DI, Akca O. The timing of acupuncture stimulation does not influence anesthetic requirement. Anesth Analg 2005;100:387–92
17.Jones RM, Cashman JN, Eger EI II, Damask MC, Johnson BH. Kinetics and potency of desflurance (I-653) in volunteers. Anesth Analg 1990;70:3–7
18.Dixon WJ. Quantal-response variable experimentation: the up-and-down method. Stat Endocrinol 1970:251–67
19.Dixon WJ, Mood AM. A method for obtaining and analyzing sensitivity data. J Am Stat Assoc 1948;43:109–26
20.Efron B, Gibshirani RJ. An introduction to bootstrap. New York: Chapman & Hall, 1993
21.Fahey MR, Sessler DI, Cannon JE, Brady K, Støen R, Miller RD. Atracurium, vecuronium, and pancuronium do not alter the minimum alveolar concentration of halothane in humans. Anesthesiology 1989;71:53–6
22.Paul M, Fisher DM. Are estimates of MAC reliable? Anesthesiology 2001;95:1362–70
23.Wadhwa A, Durrani J, Sengupta P, Doufas AG, Sessler DI. Women have the same desflurane minimum alveolar concentration as men: a prospective study. Anesthesiology 2003;99:1062–5
24.Zbinden AM, Maggiorini M, Petersen-Felix S, Lauber R, Thomson DA, Minder CE. Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. I. Motor reactions. Anesthesiology 1994;80:253–60
25.Rampil IJ, Lockhart SH, Zwass MS, Peterson N, Yasuda N, Eger EI II, Weiskopf RB, Damask MC. Clinical characteristics of desflurane in surgical patients: minimum alveolar concentration. Anesthesiology 1991;74:429–33
26.Matteo RS, Pua EK, Khambatta HJ, Spector S. Cerebrospinal fluid levels of d-tubocurarine in man. Anesthesiology 1977;46:396–9
27.Mammoto T, Yamamoto Y, Kagawa K, Hayashi Y, Mashimo T, Yoshiya I, Yamatodani A. Interactions between neuronal histamine and halothane anesthesia in rats. J Neurochem 1997;69:406–11
28.Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998;89:980–1002
29.Sebel PS, Lang E, Rampil IJ, White PF, Cork R, Jopling M, Smith NT, Glass PS, Manberg P. A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect. Anesth Analg 1997;84:891–9
30.Alkire MT. Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers. Anesthesiology 1998;89:323–33
31.Rampil IJ, Matteo RS. Changes in EEG spectral edge frequency correlate with the hemodynamic response to laryngoscopy and intubation. Anesthesiology 1987;67:139–42
32.Kochs E, Bischoff P, Pichlmeier U, Schulte am Esch J. Surgical stimulation induces changes in brain electrical activity during isoflurane/nitrous oxide anesthesia. A topographic electroencephalographic analysis. Anesthesiology 1994;80:1026–34
33.Hagihira S, Takashina M, Mori T, Ueyama H, Mashimo T. Electroencephalographic bicoherence is sensitive to noxious stimuli during isoflurane or sevoflurane anesthesia. Anesthesiology 2004;100:818–25
34.Kox WJ, von Heymann C, Heinze J, Prichep LS, John ER, Rundshagen I. Electroencephalographic mapping during routine clinical practice: cortical arousal during tracheal intubation? Anesth Analg 2006;102:825–31
35.Ekman A, Stalberg E, Sundman E, Eriksson LI, Brudin L, Sandin R. The effect of neuromuscular block and noxious stimulation on hypnosis monitoring during sevoflurane anesthesia. Anesth Analg 2007;105:688–95
36.Ropcke H, Rehberg B, Koenen-Bergmann M, Bouillon T, Bruhn J, Hoeft A. Surgical stimulation shifts EEG concentration-response relationship of desflurane. Anesthesiology 2001;94:390–9
37.Richmond CE, Matson A, Thornton C, Dore CJ, Newton DE. Effect of neuromuscular block on depth of anaesthesia as measured by the auditory evoked response. Br J Anaesth 1996;76:446–8
38.Kochs E, Kalkman CJ, Thornton C, Newton D, Bischoff P, Kuppe H, Abke J, Konecny E, Nahm W, Stockmanns G. Middle latency auditory evoked responses and electroencephalographic derived variables do not predict movement to noxious stimulation during 1 minimum alveolar anesthetic concentration isoflurane/nitrous oxide anesthesia. Anesth Analg 1999;88:1412–17
39.Sleigh JW, Steyn-Ross DA, Steyn-Ross ML, Williams ML, Smith P. Comparison of changes in electroencephalographic measures during induction of general anaesthesia: influence of the gamma frequency band and electromyogram signal. Br J Anaesth 2001;86:50–8
40.Gross DW, Gotman J. Correlation of high-frequency oscillations with the sleep-wake cycle and cognitive activity in humans. Neuroscience 1999;94:1005–18
41.Chortkoff BS, Gonsowski CT, Bennett HL, Levinson B, Crankshaw DP, Dutton RC, Ionescu P, Block RI, Eger EI II. Subanesthetic concentrations of desflurane and propofol suppress recall of emotionally charged information. Anesth Analg 1995;81:728–36
42.Munte S, Munte TF, Grotkamp J, Haeseler G, Raymondos K, Piepenbrock S, Kraus G. Implicit memory varies as a function of hypnotic electroencephalogram stage in surgical patients. Anesth Analg 2003;97:132–8
43.Lequeux PY, Sosnowski M, Morrison S, Bejjani G, Cantraine F, Barvais L. The effect of analgesic state on implicit learning during propofol anesthesia in volunteers. Acta Anaesthesiol Belg 2006;57:355–9
44.Brunner MD, Nathwani D, Rich PA, Thornton C, Dore CJ, Newton DE. Effect of suxamethonium on the auditory evoked response in humans. Br J Anaesth 1996;76:34–7
45.Libet B, Alberts WW, Wright EW Jr, Feinstein B. Responses of human somatosensory cortex to stimuli below threshold for conscious sensation. Science 1967;158:1597–600
46.Jessop J, Jones JG. Conscious awareness during general anaesthesia—what are we attempting to monitor? Br J Anaesth 1991;66:635–7
47.Antognini JF, Carstens E, Atherley R. Does the immobilizing effect of thiopental in brain exceed that of halothane? Anesthesiology 2002;96:980–6
48.Antognini JF, Jinks SL, Atherley R, Clayton C, Carstens E. Spinal anaesthesia indirectly depresses cortical activity associated with electrical stimulation of the reticular formation. Br J Anaesth 2003;91:233–8
49.Antognini JF, Berg K. Cardiovascular responses to noxious stimuli during isoflurane anesthesia are minimally affected by anesthetic action in the brain. Anesth Analg 1995;81:843–8
50.Gibbs NM, Larach DR, Schuler HG. The effect of neuromuscular blockade with vecuronium on hemodynamic responses to noxious stimuli in the rat. Anesthesiology 1989;71:214–7
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