Neuroscience in Anesthesiology and Perioperative Medicine Section Editor: Gregory J. Crosby
Dexmedetomidine Does Not Affect Evoked Potentials During Spine Surgery Irene Rozet, MD,*† Julia Metzner, MD,* Marcia Brown, MD,* Miriam M. Treggiari, MD, PhD,* Jefferson C. Slimp, PhD,‡ Greg Kinney, PhD,‡ Deepak Sharma, MD,* Lorri A. Lee, MD,§ and Monica S. Vavilala, MD∥ BACKGROUND: The effect of dexmedetomidine on evoked potentials (EPs) has not been elucidated. We aimed to investigate the effect of dexmedetomidine on somatosensory, motor, and visual EPs. METHODS: After IRB approval, 40 adult patients scheduled for elective spine surgery using total IV anesthesia with propofol and remifentanil were randomly assigned to receive either dexmedetomidine (n = 20) or placebo (n = 20) in a double-blind, placebo-controlled trial. After obtaining informed consent, positioning, and baseline EPs recording, patients were randomly assigned to either IV dexmedetomidine 0.6 μg/kg infused over 10 minutes, followed by 0.6 μg/kg/h, or a corresponding volume of IV normal saline (placebo). EP measures at 60 ± 30 minutes after initiation of study drug were defined as T1 and at 150 ± 30 minutes were defined as T2. Changes from baseline to T1 (primary end point) and from baseline to T2 (secondary end point) in EP latencies (milliseconds) and amplitudes (microvolts) were compared between groups. Data presented as mean ± SD (95% confidence interval). RESULTS: Data from 40 patients (dexmedetomidine: n = 20; age, 54 ± 3 years; 10 males; placebo: n = 20; age, 52 ± 2 years; 5 males) were analyzed. There was no difference between dexmedetomidine versus placebo groups in primary end points: change of somatosensory EPs at T1, latency: 0.01 ± 1.3 (−0.64, 0.65) vs 0.01 ± 1.3 (−0.64, 0.65), P = 0.43 (−1.24, 0.45); amplitude: 0.03 ± 0.14 (−0.06, 0.02) vs −0.01 ± 0.13 (−0.07, 0.05), P = 0.76 (−0.074, 0.1); motor EPs amplitude at T1: 65.1 ± 194.8 (−35, 165; n = 18) vs 109.2 ± 241.4 (−24, 243; n = 16), P = 0.57 (−113.5, 241.57); visual EPs at T1 (right eye), amplitude: 2.3 ± 3.6 (−0.4, 5.1; n = 11) vs 0.3 ± 6.0 (−3.3, 3.9; n = 16), P = 0.38 (−6.7, 2.6); latency N1: 2.3 ± 3.6 (−0.4, 5.1) vs 0.3 ± 6.0 (−3.3, 3.9), P = 0.38 (−6.7, 2.6); latency P1: −1.6 ± 13.4 (−11.9, 8.7) vs −1.4 ± 8.1 (−6.3, 3.5), P = 0.97 (−9.3, 9.7) or secondary end points. There were no differences between right and left visual EPs either at T1 or at T2. CONCLUSIONS: In clinically relevant doses, dexmedetomidine as an adjunct to total IV anesthesia does not seem to alter EPs and therefore can be safely used during surgeries requiring monitoring of EPs. (Anesth Analg 2015;121:492–501)
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onitoring of evoked potentials (EPs) improves neurologic outcome after spine surgery, and its use has increased substantially over the past couple of decades.1 The quality of intraoperative recording of EPs depends on multiple factors and differs between modalities.1–3 To potentiate reliability of EPs during spine surgery, simultaneous multimodal monitoring, including somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs), along with electromyography is
From the *Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington; †Department of Veterans Affairs, Puget Sound Health Care System, Seattle, Washington; ‡Department of Neurosurgery and Rehabilitation Medicine, University of Washington, Seattle, Washington; §Department of Anesthesiology and Pain Medicine and Neurosurgery, University of Washington, Seattle, Washington; and ∥Department of Anesthesiology and Pain Medicine, Neurosurgery and Pediatrics, University of Washington, Seattle, Washington. Accepted for publication March 13, 2015.
Funding: Supported by grant-in-aid, Hospira, Inc., and departmental funds from the Harborview Anesthesia Research Center, Seattle, WA. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Irene Rozet, MD, Department of Veterans Affairs, Puget Sound Health Care System, ANES - 112, 1660 S Columbian Way, Seattle, WA 98015. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000840
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recommended1,4 and is often used in modern practice for spinal instrumentation in the cervical and thoracic regions. Because most common anesthetics suppress EPs, a strategy that balances adequate anesthesia with the ability to obtain a reliable quality of EPs throughout surgery represents a challenging task. Inhibition of SSEPs and MEPs by common anesthetics is both agent and dose specific and is more profound with the deepening of anesthesia. At clinically relevant doses, however, propofol is superior to inhaled anesthetic in recording adequate SSEPs and MEPs5–9; therefore, currently, total IV anesthesia (TIVA) is considered as a preferable anesthetic technique when multimodal monitoring of EPs is required. The neuroanesthesia community has been looking into various anesthesia-sparing adjuncts, which may preserve EPs. Just recently, lidocaine was reported to preserve both SSEPS and MEPs while reducing doses of propofol and opioid as a part of TIVA.10 Dexmedetomidine, an α-2 agonist, differs from common anesthetics by its non–γaminobutyric acid (GABA) mechanisms of sedation and anxiolysis. At clinically relevant doses, it provides hemodynamic stability and a natural sleep-like pattern of breathing with minimal, if any, concomitant respiratory depression and, possibly, some analgesia. Adding dexmedetomidine to GABAergic anesthetics potentiates the hypnotic effect of the latter and reduces the induction dose of propofol by nearly half.11 Although some contradictory data have been August 2015 • Volume 121 • Number 2
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reported on dexmedetomidine’s effect on MEPs,12–16 its effect has never been studied in a randomized, controlled fashion and remains largely unknown. Monitoring of visual evoked potentials (VEPs) was introduced into intraoperative practice in the early 1970s, but its use has not been widely accepted because of the inconsistency and questionable reliability of the recordings.17–22 However, this modality may serve as a unique tool for monitoring visual pathways, particularly during lengthy prone spine surgeries that are known to be high risk for the devastating complication of postoperative blindness.23 The feasibility of recording VEPs and the effect of the currently used anesthetics on VEPs intraoperatively have not been recently investigated, leading to a revived interest in studying the validity and reliability of VEPs for detecting injury to the visual pathways.24–26 This randomized, placebocontrolled, double-blind study was designed to evaluate the effect of a clinically relevant dose of dexmedetomidine as an adjunct to TIVA on the SSEPs, MEPs, and VEPs during spine surgery.
METHODS
The study was approved by our IRB, and written informed consent was obtained from all participants during the preoperative visit. Our study was registered before patient enrollment at CinicalTrials.gov on June 27, 2007: ClinicalTrials. gov Identifier: NCT00494832. ASA physical status I to III patients aged 18 years or older scheduled for elective spine surgery in supine, prone, or lateral position requiring intraoperative monitoring of SSEPs and MEPs were included. Exclusion criteria were patients older than 80 years, ASA physical status >III, preoperative neurologic deficit, cortical blindness, retinal or optic neuropathy, glaucoma, cataracts, diabetes, psychiatric disorders, morbid obesity (body mass index >40), acute and subacute coronary syndrome, and chronic renal or hepatic insufficiency. This was a rando mized, double-blind, placebo-controlled study. The study was performed at the 2 hospitals affiliated with the University of Washington: (1) 20 patients were randomly assigned at the Trauma Level 1 Harborview Medical Center and (2) 20 patients were randomly assigned at the University of Washington Medical Center. Randomization was stratified by institution and managed by the investigational drug services at the hospital pharmacy’s research unit. After obtaining informed consent, eligible participants were randomized, using a random number generator, to receive either placebo (normal saline) or dexmedetomidine.
Study Protocol
All subjects received premedication with IV midazolam with the dose at the discretion of an attending anesthesio logist, but not >0.05 mg/kg. After application of standard ASA monitoring and bispectral index (BIS) montage, general anesthesia was induced according to the attending anesthesio logist’s preferences. All patients received an arterial line, which was inserted before or after an induction to anesthesia. TIVA with propofol and remifentanil was used for maintenance of anesthesia, using infusion pump (ALARIS® Signature Edition® Gold Infusion System, CareFusion, San Diego, CA) and adjusted to maintain the BIS between 30 and 55. To prevent undesirable awareness
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at any point of the study, an infusion rate of propofol and remifentanil 0.6 μg/kg is administered quickly. Adolescents also may be more sensitive to either dexmedetomidine or the combination of dexmedetomidine and propofol, than adults.
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Dexmedetomidine and Evoked Potentials in Spine Surgery
Table 2. Hemodynamic and Concomitant Medications Data of Patients Receiving Dexmedetomidine or Placebo Systolic blood pressure (mm Hg) Baseline T1 T2 Diastolic blood pressure (mm Hg) Baseline T1 T2 Mean arterial pressure (mm Hg) Baseline T1 T2 Heart rate (bpm) Baseline T1 T2 Bispectral index Baseline T1 T2 Core temperature (°C) Baseline T1 T2 Propofol (μg/kg/min) Baseline T1 T2 Remifentanil (μg/kg/min) Baseline T1 T2 Any use of phenylephrine or ephedrine, n (%) Bolus Infusion (phenylephrine)
Placebo (n = 20)
Dexmedetomidine (n = 20)
P value
107 ± 16 113 ± 10 111 ± 11
115 ± 20 121 ± 14 120 ± 12
0.13 0.03 0.02
65 ± 10 65 ± 7 64 ± 10
65 ± 10 70 ± 8 70 ± 8
0.78 0.04 0.07
79 ± 11 81 ± 6 80 ± 8
82 ± 12 87 ± 9 87 ± 8
0.36 0.02 0.02
67 ± 12 69 ± 14 73 ± 14
67 ± 12 67 ± 10 72 ± 12
0.99 0.60 0.88
37 ± 8 42 ± 10 41 ± 8
39 ± 12 36 ± 9 35 ± 10
0.57 0.10 0.11
35.6 ± 0.7 35.9 ± 0.6 36.5 ± 0.7
35.7 ± 0.7 35.9 ± 0.6 36.5 ± 0.8
0.66 0.86 0.86
146 ± 33 140 ± 25 144 ± 26
133 ± 21 134 ± 19 132 ± 16
0.14 0.43 0.10
0.19 ± 0.09 0.23 ± 0.12 0.22 ± 0.11
0.21 ± 0.13 0.24 ± 0.12 0.23 ± 0.12
0.65 0.90 0.82
7 (35) 11 (55)
8 (40) 9 (45)
0.74 0.53
T1 = average of measures taken at 30, 60, and 90 min after initiation of study drug (3 measures); T2 = average of measures taken at 120, 150, and 180 min after initiation of study drug (3 measures).
The limitation of this trial is that it did not have sufficient power to detect the smaller differences in latency and amplitude of EPs. However, we did not find any suggestion of even a trend in differences between dexmedetomidine and placebo on the main study end points. The results of this study indicated a lack of deleterious effect on SSEP or MEPs, suggesting that when using dexmedetomidine, SSEPs and MEPs remain stable and that intraoperative monitoring remains reliable. Similarly, there were no adverse effects of dexmedetomidine on VEPs. We successfully obtained consistent VEP recording in 74% of cases; in the reminder of cases, recording was either not obtainable at the baseline or not consistent, independently of whether dexmedetomidine was used. Since the introduction of an intraoperative VEPs moni toring in early 1970s, the diagnostic and prognostic values of the modality has been questioned.17–23 It is also unclear which anesthetic regimen provides the most favorable conditions for obtaining VEPs.20,21,27–29 Inhaled anesthetics have been suggested to have more profound inhibition of VEPs than propofol,20,26,30 but both consistent and nonfading VEPs were obtained with various inhaled anesthetics31,32 and inconsistent VEPs have been reported with TIVA.33,34 High sensitivity of VEPs to vital signs changes,34,35 genuine technology flaws, and technical aspects of VEPs application in
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the intraoperative environment have been suggested as reasons for failure.20–25,34,35 The use of newly developed lightemitting diodes for VEP stimulation36 was recently reported to provide a high validity and reliability of VEPs for intraoperative guidance and as a predictive tool for postoperative visual problems.37,38 Because we did not control for the awake VEPs and did not perform electroretinography to verify that stimulus reached patients’ retina, which could have helped to identify technology flaws, we cannot comment on possible reasons for failure to obtain baseline VEPs. The results of our study suggest that if baseline VEPs were obtainable, dexmedetomidine did not seem to affect VEPs intraoperatively, which parallels other reports using technology similar to our study.31,32 VEP monitoring remains controversial for both the diagnostic and the prognostic value of the modality. Our study included an assessment of depth of anesthesia. Because the anesthesia team was blinded to the study drug, a misinterpretation of hemodynamic changes might lead to subsequent erroneous management of TIVA. To avoid accidental swings in anesthetic depth, we maintained the BIS within a range of 35 to 55, as a guide for adjusting propofol and remifentanil infusion rates. Our patients were not paralyzed, which may have improved BIS accuracy.
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Figure 2. Evoked potentials in study groups. Latency was measured in milliseconds, and amplitude was measured in microvolts. Data presented as mean ± SD. T0 = baseline; T15 = average of measurements in interval between T0 and next 15 minutes; T30 = average of measurements in interval between T15 and next 15 minutes; T60 = average of measurements in interval between T30 and next 30 minutes; T90 = average of measurements in interval between T60 and next 30 minutes; T120 = average of measurements in interval between T90 and next 30 minutes, and so on. Somatosensory Evoked Potentials (SSEPs). Latency P37: A, left side; B, right side; Amplitude N33P37: C, left side; D, right side.
Figure 2. (Continued). Motor Evoked Potentials (MEPs). Amplitude, peak to peak, abductor hallucis: A, left side; B, right side.
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Dexmedetomidine and Evoked Potentials in Spine Surgery
Figure 2. (Continued). Visual Evoked Potentials (VEPs). Latency N1: A, left eye; B, right eye; Latency P1: C, left eye; 3D, right eye; Amplitude N1-P1: E, left eye; F, right eye.
Undoubtedly, the BIS is not an ideal monitoring of anes thesia depth with high intersubject variability.39 As the plasma concentrations of propofol and dexmedetomidine were not measured, the lower threshold of the doses of both medications have been established intuitively rather than scientifically to prevent accidental awareness. We did not observe any cases of awareness in our study. In fact, much less conservative doses of propofol than ours have been reported to be safe, and it is possible that the lower dose of propofol could be used safely, if dexmedetomidine is infused concomitantly.40
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Our protocol included maintaining normothermia and hemodynamic stability. Although strict criteria for the management of hemodynamics were developed, which resulted in comparable doses of propofol, remifentanil, and vasopressors between placebo and dexmedetomidine groups, a higher blood pressure with dexmedetomidine, compared with placebo, was observed, which might improve the quality of EPs. This observation most probably reflected a combination of some degree of diminished propofol-induced vasodilatation along with peripheral vasoconstriction as a result of α-2 β effect of dexmedetomidine.41 However, it is
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Table 3. Primary Outcomes SSEP Latency P37 Amplitude N33-P37 MEP Amplitude VEP Latency N1 Right eye Left eye Latency P1 Right eye Left eye Amplitude N1-P1 Right eye Left eye
Placebo n = 20 0.01 ± 1.3 (−0.64, 0.65) −0.01 ± 0.13 (−0.07, 0.05) n = 16 109.2 ± 241.4 (−24, 243) n = 14
Dexmedetomidine n = 20 0.4 ± 1.2 (−0.2, 0.62) −0.03 ± 0.14 (−0.06, 0.02) n = 18 65.1 ± 194.8 (−35, 165) n = 11
P value (95% CI)
0.3. ± 6.0 (−3.3, 3.9) 0.6 ± 6.2 (−3.2, 4.4)
2.3 ± 3.6 (−0.4, 5.1) −0.17± 2.5 (−2.1, 1.7)
0.38 (−6.7, 2.6) 0.36 (−6.7, 26)
−1.4 ± 8.1 (−6.3, 3.5) 0.7 ± 6.2 (−3.1, 4.4)
−1.6 ± 13.4 (−11.9, 8.7) 1.4 ± 5.4 (−2.7, 5.5)
0.97 (−9.3, 9.7) 0.78 (−6.0, 4.7)
−0.34 ± 1.2 (−1.1, 0.4) 0.04 ± 1.8 (−1.1, 1.15)
−0.6 ± 1.6 (−1.9, 0.69) −0.23 ± 1.1 (−1.1, 0.6)
0.7 (−1.0, 1.5) 0.69 (−1.1, 1.67)
0.43 (−1.24, 0.45) 0.76 (−0.074, 0.1) 0.57 (−113.5, 241.57)
Primary outcome is a change from baseline to T1. Latency was measured in milliseconds, and amplitude was measured in microvolts. Data are presented as mean ± SD and 95% CI. CI = confidence interval; MEP = motor evoked potential; SSEP = somatosensory evoked potential; T1 = average of measures taken at 30, 60, and 90 min after initiation of study drug (1 minimum and 3 maximum measures); VEP = visual evoked potential.
Table 4. Secondary Outcomes SSEP Latency P37 Amplitude N33-P37 MEP Amplitude VEP Latency N1 Right eye Left eye Latency P1 Right eye Left eye Amplitude N1-P1 Right eye Left eye
Placebo n = 16 −0.82 ± 1.87 0.94 ± 4.07 n = 16 113.5 ± 217.5 n = 13
Dexmedetomidine n = 18 −0.66 ± 1.59 −0.04 ± 0.18 n = 16 −116.7 ± 136.3 n = 11
P value
−2.9 ± 7.6 −3.5 ± 5
1.7 ± 7.3 −1.8 ± −4
0.2 0.4
−3.8 ± 9 −2.8 ± −8.3
1.7 ± 5.8 −0.5 ± 5.8
0.15 0.5
−03 ± −0.8 −0.1 ± −1.1
−0.5 ± 2.6 −0.5 ± 2.1
0.76 0.6
0.79 0.31 0.33
Secondary outcome is a change from baseline to T2. Latency was measured in milliseconds, and amplitude was measured in microvolts. Data are presented as mean ± SD. MEP = motor evoked potential; SSEP = somatosensory evoked potential; T2 = average of measures taken at 120, 150, and 180 min after initiation of study drug (1 minimum and 3 maximum measures); VEP = visual evoked potential.
unlikely that this finding has clinical relevance in our study, because blood pressure was maintained within the normal range in both groups. The core temperature at baseline and T1 was similar in both groups and, therefore, could not have affected the primary outcome. Normalization of temperature at T2, which might improve quality of EPs, was similar in both groups and, therefore, could not have influenced the secondary outcome in our study. In conclusion, we found that dexmedetomidine as an adjunct to TIVA does not seem to impair SSEPs, MEPs, and VEP during the first 3 hours of infusion at dose of 0.6 μg /kg/h and may be safely used in surgeries requiring such monitoring. Together, these findings suggest that dexmedetomidine may be safely used during spine surgeries where patients are undergoing multimodal intraoperative EP monitoring. Further studies are required to elucidate the validity of intraoperative VEP monitoring as a prognostic modality of perioperative visual disturbances. E August 2015 • Volume 121 • Number 2
DISCLOSURES
Name: Irene Rozet, MD. Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript. Attestation: Irene Rozet approved the final manuscript and is the archival author. Name: Julia Metzner, MD. Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript. Attestation: Julia Metzner approved the final manuscript. Name: Marcia Brown, MD. Contribution: This author helped design the study and conduct the study. Attestation: Marcia Brown approved the final manuscript. Name: Miriam M. Treggiari, MD, PhD. Contribution: This author helped analyze the data and prepare the manuscript. Attestation: Miriam M. Treggiari approved the final manuscript.
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Dexmedetomidine and Evoked Potentials in Spine Surgery
Name: Jefferson C. Slimp, PhD. Contribution: This author helped analyze the data and prepare the manuscript. Attestation: Jefferson C. Slimp approved the final manuscript. Name: Greg Kinney, PhD. Contribution: This author helped collect the data, analyze the data, and prepare the manuscript. Attestation: Greg Kinney approved the final manuscript. Name: Deepak Sharma, MD. Contribution: This author helped design the study and prepare the manuscript. Attestation: Deepak Sharma approved the final manuscript. Name: Lorri A. Lee, MD. Contribution: This author helped design the study. Attestation: Lorri A. Lee approved the final manuscript. Name: Monica S. Vavilala, MD. Contribution: This author helped design the study and prepare the manuscript. Attestation: Monica S. Vavilala approved the final manuscript. This manuscript was handled by: Gregory J. Crosby, MD. ACKNOWLEDGMENTS
We thank all our colleagues for collaboration with the study. Our special gratitude goes to the surgeons of the Orthopedic and Neurosurgery Departments for their assistance in patients’ enrollment at 1 of the 2 study sites (UWMC). Without their help this study would not be completed. REFERENCES 1. Sloan TB, Janik D, Jameson L. Multimodality monitoring of the central nervous system using motor-evoked potentials. Curr Opin Anaesthesiol 2008;21:560–4 2. Chen X, Sterio D, Ming X, Para DD, Butusova M, Tong T, Beric A. Success rate of motor evoked potentials for intraoperative neurophysiologic monitoring: effects of age, lesion location, and preoperative neurologic deficits. J Clin Neurophysiol 2007;24:281–5 3. Deiner SG, Kwatra SG, Lin HM, Weisz DJ. Patient characteristics and anesthetic technique are additive but not synergistic predictors of successful motor evoked potential monitoring. Anesth Analg 2010;111:421–5 4. Deletis V, Sala F. Intraoperative neurophysiological monitoring of the spinal cord during spinal cord and spine surgery: a review focus on the corticospinal tracts. Clin Neurophysiol 2008;119:248–64 5. Deletis V, Kiprovski K, Morota N. The influence of halothane, enflurane, and isoflurane on motor evoked potentials. Neurosurgery 1993;33:173–4 6. Pelosi L, Stevenson M, Hobbs GJ, Jardine A, Webb JK. Intraoperative motor evoked potentials to transcranial electrical stimulation during two anaesthetic regimens. Clin Neurophysiol 2001;112:1076–87 7. Lotto ML, Banoub M, Schubert A. Effects of anesthetic agents and physiologic changes on intraoperative motor evoked potentials. J Neurosurg Anesthesiol 2004;16:32–42 8. Deiner S. Highlights of anesthetic considerations for intraoperative neuromonitoring. Semin Cardiothorac Vasc Anesth 2010;14:51–3 9. Clapcich AJ, Emerson RG, Roye DP Jr, Xie H, Gallo EJ, Dowling KC, Ramnath B, Heyer EJ. The effects of propofol, small-dose isoflurane, and nitrous oxide on cortical somatosensory evoked potential and bispectral index monitoring in adolescents undergoing spinal fusion. Anesth Analg 2004;99:1334–40 10. Sloan TB, Mongan P, Lyda C, Koht A. Lidocaine infusion adjunct to total intravenous anesthesia reduces the total dose of propofol during intraoperative neurophysiological monitoring. J Clin Monit Comput 2014;28:139–47 11. Dutta S, Karol MD, Cohen T, Jones RM, Mant T. Effect of dexmedetomidine on propofol requirements in healthy subjects. J Pharm Sci 2001;90:172–81
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34. Wiedemayer H, Fauser B, Armbruster W, Gasser T, Stolke D. Visual evoked potentials for intraoperative neurophysiologic monitoring using total intravenous anesthesia. J Neurosurg Anesthesiol 2003;15:19–24 35. Wiedemayer H, Fauser B, Sandalcioglu IE, Armbruster W, Stolke D. Observations on intraoperative monitoring of visual pathways using steady-state visual evoked potentials. Eur J Anaesthesiol 2004;21:429–33 36. Sasaki T, Ichikawa T, Sakuma J, Suzuki K, Matsumoto M, Itakura T, Kodama N, Murakawa M. Intraoperative monitoring of visual evoked potentials [in Japanese]. Masui 2006;55:302–13 37. Sasaki T, Itakura T, Suzuki K, Kasuya H, Munakata R, Muramatsu H, Ichikawa T, Sato T, Endo Y, Sakuma J, Matsumoto M. Intraoperative monitoring of visual evoked potential: introduction of a clinically useful method. J Neurosurg 2010;112:273–84
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38. Kodama K, Goto T, Sato A, Sakai K, Tanaka Y, Hongo K. Standard and limitation of intraoperative monitoring of the visual evoked potential. Acta Neurochir 2010;152:643–8 39. Kaskinoro K, Maksimow A, Långsjö J, Aantaa R, Jääskeläinen S, Kaisti K, Särkelä M, Scheinin H. Wide inter-individual variability of bispectral index and spectral entropy at loss of consciousness during increasing concentrations of dexmedetomidine, propofol, and sevoflurane. Br J Anaesth 2011;107:573–80 40. Metzner J, Kent CD, Slimp J, Tredway T, Domino KB. Effects of dexmedetomidine on motor evoked potential monitoring during spine surgery. Anesthesiology 2008;109:A243 41. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000;93:382–94
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Dexmedetomidine Does Not Affect Evoked Potentials During Spine Surgery Irene Rozet, MD,*† Julia Metzner, MD,* Marcia Brown, MD,* Miriam M. Treggiari, MD, PhD,* Jefferson C. Slimp, PhD,‡ Greg Kinney, PhD,‡ Deepak Sharma, MD,* Lorri A. Lee, MD,§ and Monica S. Vavilala, MD∥ BACKGROUND: The effect of dexmedetomidine on evoked potentials (EPs) has not been elucidated. We aimed to investigate the effect of dexmedetomidine on somatosensory, motor, and visual EPs. METHODS: After IRB approval, 40 adult patients scheduled for elective spine surgery using total IV anesthesia with propofol and remifentanil were randomly assigned to receive either dexmedetomidine (n = 20) or placebo (n = 20) in a double-blind, placebo-controlled trial. After obtaining informed consent, positioning, and baseline EPs recording, patients were randomly assigned to either IV dexmedetomidine 0.6 μg/kg infused over 10 minutes, followed by 0.6 μg/kg/h, or a corresponding volume of IV normal saline (placebo). EP measures at 60 ± 30 minutes after initiation of study drug were defined as T1 and at 150 ± 30 minutes were defined as T2. Changes from baseline to T1 (primary end point) and from baseline to T2 (secondary end point) in EP latencies (milliseconds) and amplitudes (microvolts) were compared between groups. Data presented as mean ± SD (95% confidence interval). RESULTS: Data from 40 patients (dexmedetomidine: n = 20; age, 54 ± 3 years; 10 males; placebo: n = 20; age, 52 ± 2 years; 5 males) were analyzed. There was no difference between dexmedetomidine versus placebo groups in primary end points: change of somatosensory EPs at T1, latency: 0.01 ± 1.3 (−0.64, 0.65) vs 0.01 ± 1.3 (−0.64, 0.65), P = 0.43 (−1.24, 0.45); amplitude: 0.03 ± 0.14 (−0.06, 0.02) vs −0.01 ± 0.13 (−0.07, 0.05), P = 0.76 (−0.074, 0.1); motor EPs amplitude at T1: 65.1 ± 194.8 (−35, 165; n = 18) vs 109.2 ± 241.4 (−24, 243; n = 16), P = 0.57 (−113.5, 241.57); visual EPs at T1 (right eye), amplitude: 2.3 ± 3.6 (−0.4, 5.1; n = 11) vs 0.3 ± 6.0 (−3.3, 3.9; n = 16), P = 0.38 (−6.7, 2.6); latency N1: 2.3 ± 3.6 (−0.4, 5.1) vs 0.3 ± 6.0 (−3.3, 3.9), P = 0.38 (−6.7, 2.6); latency P1: −1.6 ± 13.4 (−11.9, 8.7) vs −1.4 ± 8.1 (−6.3, 3.5), P = 0.97 (−9.3, 9.7) or secondary end points. There were no differences between right and left visual EPs either at T1 or at T2. CONCLUSIONS: In clinically relevant doses, dexmedetomidine as an adjunct to total IV anesthesia does not seem to alter EPs and therefore can be safely used during surgeries requiring monitoring of EPs. (Anesth Analg 2015;121:492–501)
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onitoring of evoked potentials (EPs) improves neurologic outcome after spine surgery, and its use has increased substantially over the past couple of decades.1 The quality of intraoperative recording of EPs depends on multiple factors and differs between modalities.1–3 To potentiate reliability of EPs during spine surgery, simultaneous multimodal monitoring, including somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs), along with electromyography is
From the *Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington; †Department of Veterans Affairs, Puget Sound Health Care System, Seattle, Washington; ‡Department of Neurosurgery and Rehabilitation Medicine, University of Washington, Seattle, Washington; §Department of Anesthesiology and Pain Medicine and Neurosurgery, University of Washington, Seattle, Washington; and ∥Department of Anesthesiology and Pain Medicine, Neurosurgery and Pediatrics, University of Washington, Seattle, Washington. Accepted for publication March 13, 2015.
Funding: Supported by grant-in-aid, Hospira, Inc., and departmental funds from the Harborview Anesthesia Research Center, Seattle, WA. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Irene Rozet, MD, Department of Veterans Affairs, Puget Sound Health Care System, ANES - 112, 1660 S Columbian Way, Seattle, WA 98015. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000840
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recommended1,4 and is often used in modern practice for spinal instrumentation in the cervical and thoracic regions. Because most common anesthetics suppress EPs, a strategy that balances adequate anesthesia with the ability to obtain a reliable quality of EPs throughout surgery represents a challenging task. Inhibition of SSEPs and MEPs by common anesthetics is both agent and dose specific and is more profound with the deepening of anesthesia. At clinically relevant doses, however, propofol is superior to inhaled anesthetic in recording adequate SSEPs and MEPs5–9; therefore, currently, total IV anesthesia (TIVA) is considered as a preferable anesthetic technique when multimodal monitoring of EPs is required. The neuroanesthesia community has been looking into various anesthesia-sparing adjuncts, which may preserve EPs. Just recently, lidocaine was reported to preserve both SSEPS and MEPs while reducing doses of propofol and opioid as a part of TIVA.10 Dexmedetomidine, an α-2 agonist, differs from common anesthetics by its non–γaminobutyric acid (GABA) mechanisms of sedation and anxiolysis. At clinically relevant doses, it provides hemodynamic stability and a natural sleep-like pattern of breathing with minimal, if any, concomitant respiratory depression and, possibly, some analgesia. Adding dexmedetomidine to GABAergic anesthetics potentiates the hypnotic effect of the latter and reduces the induction dose of propofol by nearly half.11 Although some contradictory data have been August 2015 • Volume 121 • Number 2
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reported on dexmedetomidine’s effect on MEPs,12–16 its effect has never been studied in a randomized, controlled fashion and remains largely unknown. Monitoring of visual evoked potentials (VEPs) was introduced into intraoperative practice in the early 1970s, but its use has not been widely accepted because of the inconsistency and questionable reliability of the recordings.17–22 However, this modality may serve as a unique tool for monitoring visual pathways, particularly during lengthy prone spine surgeries that are known to be high risk for the devastating complication of postoperative blindness.23 The feasibility of recording VEPs and the effect of the currently used anesthetics on VEPs intraoperatively have not been recently investigated, leading to a revived interest in studying the validity and reliability of VEPs for detecting injury to the visual pathways.24–26 This randomized, placebocontrolled, double-blind study was designed to evaluate the effect of a clinically relevant dose of dexmedetomidine as an adjunct to TIVA on the SSEPs, MEPs, and VEPs during spine surgery.
METHODS
The study was approved by our IRB, and written informed consent was obtained from all participants during the preoperative visit. Our study was registered before patient enrollment at CinicalTrials.gov on June 27, 2007: ClinicalTrials. gov Identifier: NCT00494832. ASA physical status I to III patients aged 18 years or older scheduled for elective spine surgery in supine, prone, or lateral position requiring intraoperative monitoring of SSEPs and MEPs were included. Exclusion criteria were patients older than 80 years, ASA physical status >III, preoperative neurologic deficit, cortical blindness, retinal or optic neuropathy, glaucoma, cataracts, diabetes, psychiatric disorders, morbid obesity (body mass index >40), acute and subacute coronary syndrome, and chronic renal or hepatic insufficiency. This was a rando mized, double-blind, placebo-controlled study. The study was performed at the 2 hospitals affiliated with the University of Washington: (1) 20 patients were randomly assigned at the Trauma Level 1 Harborview Medical Center and (2) 20 patients were randomly assigned at the University of Washington Medical Center. Randomization was stratified by institution and managed by the investigational drug services at the hospital pharmacy’s research unit. After obtaining informed consent, eligible participants were randomized, using a random number generator, to receive either placebo (normal saline) or dexmedetomidine.
Study Protocol
All subjects received premedication with IV midazolam with the dose at the discretion of an attending anesthesio logist, but not >0.05 mg/kg. After application of standard ASA monitoring and bispectral index (BIS) montage, general anesthesia was induced according to the attending anesthesio logist’s preferences. All patients received an arterial line, which was inserted before or after an induction to anesthesia. TIVA with propofol and remifentanil was used for maintenance of anesthesia, using infusion pump (ALARIS® Signature Edition® Gold Infusion System, CareFusion, San Diego, CA) and adjusted to maintain the BIS between 30 and 55. To prevent undesirable awareness
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at any point of the study, an infusion rate of propofol and remifentanil 0.6 μg/kg is administered quickly. Adolescents also may be more sensitive to either dexmedetomidine or the combination of dexmedetomidine and propofol, than adults.
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Dexmedetomidine and Evoked Potentials in Spine Surgery
Table 2. Hemodynamic and Concomitant Medications Data of Patients Receiving Dexmedetomidine or Placebo Systolic blood pressure (mm Hg) Baseline T1 T2 Diastolic blood pressure (mm Hg) Baseline T1 T2 Mean arterial pressure (mm Hg) Baseline T1 T2 Heart rate (bpm) Baseline T1 T2 Bispectral index Baseline T1 T2 Core temperature (°C) Baseline T1 T2 Propofol (μg/kg/min) Baseline T1 T2 Remifentanil (μg/kg/min) Baseline T1 T2 Any use of phenylephrine or ephedrine, n (%) Bolus Infusion (phenylephrine)
Placebo (n = 20)
Dexmedetomidine (n = 20)
P value
107 ± 16 113 ± 10 111 ± 11
115 ± 20 121 ± 14 120 ± 12
0.13 0.03 0.02
65 ± 10 65 ± 7 64 ± 10
65 ± 10 70 ± 8 70 ± 8
0.78 0.04 0.07
79 ± 11 81 ± 6 80 ± 8
82 ± 12 87 ± 9 87 ± 8
0.36 0.02 0.02
67 ± 12 69 ± 14 73 ± 14
67 ± 12 67 ± 10 72 ± 12
0.99 0.60 0.88
37 ± 8 42 ± 10 41 ± 8
39 ± 12 36 ± 9 35 ± 10
0.57 0.10 0.11
35.6 ± 0.7 35.9 ± 0.6 36.5 ± 0.7
35.7 ± 0.7 35.9 ± 0.6 36.5 ± 0.8
0.66 0.86 0.86
146 ± 33 140 ± 25 144 ± 26
133 ± 21 134 ± 19 132 ± 16
0.14 0.43 0.10
0.19 ± 0.09 0.23 ± 0.12 0.22 ± 0.11
0.21 ± 0.13 0.24 ± 0.12 0.23 ± 0.12
0.65 0.90 0.82
7 (35) 11 (55)
8 (40) 9 (45)
0.74 0.53
T1 = average of measures taken at 30, 60, and 90 min after initiation of study drug (3 measures); T2 = average of measures taken at 120, 150, and 180 min after initiation of study drug (3 measures).
The limitation of this trial is that it did not have sufficient power to detect the smaller differences in latency and amplitude of EPs. However, we did not find any suggestion of even a trend in differences between dexmedetomidine and placebo on the main study end points. The results of this study indicated a lack of deleterious effect on SSEP or MEPs, suggesting that when using dexmedetomidine, SSEPs and MEPs remain stable and that intraoperative monitoring remains reliable. Similarly, there were no adverse effects of dexmedetomidine on VEPs. We successfully obtained consistent VEP recording in 74% of cases; in the reminder of cases, recording was either not obtainable at the baseline or not consistent, independently of whether dexmedetomidine was used. Since the introduction of an intraoperative VEPs moni toring in early 1970s, the diagnostic and prognostic values of the modality has been questioned.17–23 It is also unclear which anesthetic regimen provides the most favorable conditions for obtaining VEPs.20,21,27–29 Inhaled anesthetics have been suggested to have more profound inhibition of VEPs than propofol,20,26,30 but both consistent and nonfading VEPs were obtained with various inhaled anesthetics31,32 and inconsistent VEPs have been reported with TIVA.33,34 High sensitivity of VEPs to vital signs changes,34,35 genuine technology flaws, and technical aspects of VEPs application in
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the intraoperative environment have been suggested as reasons for failure.20–25,34,35 The use of newly developed lightemitting diodes for VEP stimulation36 was recently reported to provide a high validity and reliability of VEPs for intraoperative guidance and as a predictive tool for postoperative visual problems.37,38 Because we did not control for the awake VEPs and did not perform electroretinography to verify that stimulus reached patients’ retina, which could have helped to identify technology flaws, we cannot comment on possible reasons for failure to obtain baseline VEPs. The results of our study suggest that if baseline VEPs were obtainable, dexmedetomidine did not seem to affect VEPs intraoperatively, which parallels other reports using technology similar to our study.31,32 VEP monitoring remains controversial for both the diagnostic and the prognostic value of the modality. Our study included an assessment of depth of anesthesia. Because the anesthesia team was blinded to the study drug, a misinterpretation of hemodynamic changes might lead to subsequent erroneous management of TIVA. To avoid accidental swings in anesthetic depth, we maintained the BIS within a range of 35 to 55, as a guide for adjusting propofol and remifentanil infusion rates. Our patients were not paralyzed, which may have improved BIS accuracy.
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Figure 2. Evoked potentials in study groups. Latency was measured in milliseconds, and amplitude was measured in microvolts. Data presented as mean ± SD. T0 = baseline; T15 = average of measurements in interval between T0 and next 15 minutes; T30 = average of measurements in interval between T15 and next 15 minutes; T60 = average of measurements in interval between T30 and next 30 minutes; T90 = average of measurements in interval between T60 and next 30 minutes; T120 = average of measurements in interval between T90 and next 30 minutes, and so on. Somatosensory Evoked Potentials (SSEPs). Latency P37: A, left side; B, right side; Amplitude N33P37: C, left side; D, right side.
Figure 2. (Continued). Motor Evoked Potentials (MEPs). Amplitude, peak to peak, abductor hallucis: A, left side; B, right side.
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Dexmedetomidine and Evoked Potentials in Spine Surgery
Figure 2. (Continued). Visual Evoked Potentials (VEPs). Latency N1: A, left eye; B, right eye; Latency P1: C, left eye; 3D, right eye; Amplitude N1-P1: E, left eye; F, right eye.
Undoubtedly, the BIS is not an ideal monitoring of anes thesia depth with high intersubject variability.39 As the plasma concentrations of propofol and dexmedetomidine were not measured, the lower threshold of the doses of both medications have been established intuitively rather than scientifically to prevent accidental awareness. We did not observe any cases of awareness in our study. In fact, much less conservative doses of propofol than ours have been reported to be safe, and it is possible that the lower dose of propofol could be used safely, if dexmedetomidine is infused concomitantly.40
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Our protocol included maintaining normothermia and hemodynamic stability. Although strict criteria for the management of hemodynamics were developed, which resulted in comparable doses of propofol, remifentanil, and vasopressors between placebo and dexmedetomidine groups, a higher blood pressure with dexmedetomidine, compared with placebo, was observed, which might improve the quality of EPs. This observation most probably reflected a combination of some degree of diminished propofol-induced vasodilatation along with peripheral vasoconstriction as a result of α-2 β effect of dexmedetomidine.41 However, it is
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Table 3. Primary Outcomes SSEP Latency P37 Amplitude N33-P37 MEP Amplitude VEP Latency N1 Right eye Left eye Latency P1 Right eye Left eye Amplitude N1-P1 Right eye Left eye
Placebo n = 20 0.01 ± 1.3 (−0.64, 0.65) −0.01 ± 0.13 (−0.07, 0.05) n = 16 109.2 ± 241.4 (−24, 243) n = 14
Dexmedetomidine n = 20 0.4 ± 1.2 (−0.2, 0.62) −0.03 ± 0.14 (−0.06, 0.02) n = 18 65.1 ± 194.8 (−35, 165) n = 11
P value (95% CI)
0.3. ± 6.0 (−3.3, 3.9) 0.6 ± 6.2 (−3.2, 4.4)
2.3 ± 3.6 (−0.4, 5.1) −0.17± 2.5 (−2.1, 1.7)
0.38 (−6.7, 2.6) 0.36 (−6.7, 26)
−1.4 ± 8.1 (−6.3, 3.5) 0.7 ± 6.2 (−3.1, 4.4)
−1.6 ± 13.4 (−11.9, 8.7) 1.4 ± 5.4 (−2.7, 5.5)
0.97 (−9.3, 9.7) 0.78 (−6.0, 4.7)
−0.34 ± 1.2 (−1.1, 0.4) 0.04 ± 1.8 (−1.1, 1.15)
−0.6 ± 1.6 (−1.9, 0.69) −0.23 ± 1.1 (−1.1, 0.6)
0.7 (−1.0, 1.5) 0.69 (−1.1, 1.67)
0.43 (−1.24, 0.45) 0.76 (−0.074, 0.1) 0.57 (−113.5, 241.57)
Primary outcome is a change from baseline to T1. Latency was measured in milliseconds, and amplitude was measured in microvolts. Data are presented as mean ± SD and 95% CI. CI = confidence interval; MEP = motor evoked potential; SSEP = somatosensory evoked potential; T1 = average of measures taken at 30, 60, and 90 min after initiation of study drug (1 minimum and 3 maximum measures); VEP = visual evoked potential.
Table 4. Secondary Outcomes SSEP Latency P37 Amplitude N33-P37 MEP Amplitude VEP Latency N1 Right eye Left eye Latency P1 Right eye Left eye Amplitude N1-P1 Right eye Left eye
Placebo n = 16 −0.82 ± 1.87 0.94 ± 4.07 n = 16 113.5 ± 217.5 n = 13
Dexmedetomidine n = 18 −0.66 ± 1.59 −0.04 ± 0.18 n = 16 −116.7 ± 136.3 n = 11
P value
−2.9 ± 7.6 −3.5 ± 5
1.7 ± 7.3 −1.8 ± −4
0.2 0.4
−3.8 ± 9 −2.8 ± −8.3
1.7 ± 5.8 −0.5 ± 5.8
0.15 0.5
−03 ± −0.8 −0.1 ± −1.1
−0.5 ± 2.6 −0.5 ± 2.1
0.76 0.6
0.79 0.31 0.33
Secondary outcome is a change from baseline to T2. Latency was measured in milliseconds, and amplitude was measured in microvolts. Data are presented as mean ± SD. MEP = motor evoked potential; SSEP = somatosensory evoked potential; T2 = average of measures taken at 120, 150, and 180 min after initiation of study drug (1 minimum and 3 maximum measures); VEP = visual evoked potential.
unlikely that this finding has clinical relevance in our study, because blood pressure was maintained within the normal range in both groups. The core temperature at baseline and T1 was similar in both groups and, therefore, could not have affected the primary outcome. Normalization of temperature at T2, which might improve quality of EPs, was similar in both groups and, therefore, could not have influenced the secondary outcome in our study. In conclusion, we found that dexmedetomidine as an adjunct to TIVA does not seem to impair SSEPs, MEPs, and VEP during the first 3 hours of infusion at dose of 0.6 μg /kg/h and may be safely used in surgeries requiring such monitoring. Together, these findings suggest that dexmedetomidine may be safely used during spine surgeries where patients are undergoing multimodal intraoperative EP monitoring. Further studies are required to elucidate the validity of intraoperative VEP monitoring as a prognostic modality of perioperative visual disturbances. E August 2015 • Volume 121 • Number 2
DISCLOSURES
Name: Irene Rozet, MD. Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript. Attestation: Irene Rozet approved the final manuscript and is the archival author. Name: Julia Metzner, MD. Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript. Attestation: Julia Metzner approved the final manuscript. Name: Marcia Brown, MD. Contribution: This author helped design the study and conduct the study. Attestation: Marcia Brown approved the final manuscript. Name: Miriam M. Treggiari, MD, PhD. Contribution: This author helped analyze the data and prepare the manuscript. Attestation: Miriam M. Treggiari approved the final manuscript.
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Dexmedetomidine and Evoked Potentials in Spine Surgery
Name: Jefferson C. Slimp, PhD. Contribution: This author helped analyze the data and prepare the manuscript. Attestation: Jefferson C. Slimp approved the final manuscript. Name: Greg Kinney, PhD. Contribution: This author helped collect the data, analyze the data, and prepare the manuscript. Attestation: Greg Kinney approved the final manuscript. Name: Deepak Sharma, MD. Contribution: This author helped design the study and prepare the manuscript. Attestation: Deepak Sharma approved the final manuscript. Name: Lorri A. Lee, MD. Contribution: This author helped design the study. Attestation: Lorri A. Lee approved the final manuscript. Name: Monica S. Vavilala, MD. Contribution: This author helped design the study and prepare the manuscript. Attestation: Monica S. Vavilala approved the final manuscript. This manuscript was handled by: Gregory J. Crosby, MD. ACKNOWLEDGMENTS
We thank all our colleagues for collaboration with the study. Our special gratitude goes to the surgeons of the Orthopedic and Neurosurgery Departments for their assistance in patients’ enrollment at 1 of the 2 study sites (UWMC). Without their help this study would not be completed. REFERENCES 1. Sloan TB, Janik D, Jameson L. Multimodality monitoring of the central nervous system using motor-evoked potentials. Curr Opin Anaesthesiol 2008;21:560–4 2. Chen X, Sterio D, Ming X, Para DD, Butusova M, Tong T, Beric A. Success rate of motor evoked potentials for intraoperative neurophysiologic monitoring: effects of age, lesion location, and preoperative neurologic deficits. J Clin Neurophysiol 2007;24:281–5 3. Deiner SG, Kwatra SG, Lin HM, Weisz DJ. Patient characteristics and anesthetic technique are additive but not synergistic predictors of successful motor evoked potential monitoring. Anesth Analg 2010;111:421–5 4. Deletis V, Sala F. Intraoperative neurophysiological monitoring of the spinal cord during spinal cord and spine surgery: a review focus on the corticospinal tracts. Clin Neurophysiol 2008;119:248–64 5. Deletis V, Kiprovski K, Morota N. The influence of halothane, enflurane, and isoflurane on motor evoked potentials. Neurosurgery 1993;33:173–4 6. Pelosi L, Stevenson M, Hobbs GJ, Jardine A, Webb JK. Intraoperative motor evoked potentials to transcranial electrical stimulation during two anaesthetic regimens. Clin Neurophysiol 2001;112:1076–87 7. Lotto ML, Banoub M, Schubert A. Effects of anesthetic agents and physiologic changes on intraoperative motor evoked potentials. J Neurosurg Anesthesiol 2004;16:32–42 8. Deiner S. Highlights of anesthetic considerations for intraoperative neuromonitoring. Semin Cardiothorac Vasc Anesth 2010;14:51–3 9. Clapcich AJ, Emerson RG, Roye DP Jr, Xie H, Gallo EJ, Dowling KC, Ramnath B, Heyer EJ. The effects of propofol, small-dose isoflurane, and nitrous oxide on cortical somatosensory evoked potential and bispectral index monitoring in adolescents undergoing spinal fusion. Anesth Analg 2004;99:1334–40 10. Sloan TB, Mongan P, Lyda C, Koht A. Lidocaine infusion adjunct to total intravenous anesthesia reduces the total dose of propofol during intraoperative neurophysiological monitoring. J Clin Monit Comput 2014;28:139–47 11. Dutta S, Karol MD, Cohen T, Jones RM, Mant T. Effect of dexmedetomidine on propofol requirements in healthy subjects. J Pharm Sci 2001;90:172–81
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34. Wiedemayer H, Fauser B, Armbruster W, Gasser T, Stolke D. Visual evoked potentials for intraoperative neurophysiologic monitoring using total intravenous anesthesia. J Neurosurg Anesthesiol 2003;15:19–24 35. Wiedemayer H, Fauser B, Sandalcioglu IE, Armbruster W, Stolke D. Observations on intraoperative monitoring of visual pathways using steady-state visual evoked potentials. Eur J Anaesthesiol 2004;21:429–33 36. Sasaki T, Ichikawa T, Sakuma J, Suzuki K, Matsumoto M, Itakura T, Kodama N, Murakawa M. Intraoperative monitoring of visual evoked potentials [in Japanese]. Masui 2006;55:302–13 37. Sasaki T, Itakura T, Suzuki K, Kasuya H, Munakata R, Muramatsu H, Ichikawa T, Sato T, Endo Y, Sakuma J, Matsumoto M. Intraoperative monitoring of visual evoked potential: introduction of a clinically useful method. J Neurosurg 2010;112:273–84
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38. Kodama K, Goto T, Sato A, Sakai K, Tanaka Y, Hongo K. Standard and limitation of intraoperative monitoring of the visual evoked potential. Acta Neurochir 2010;152:643–8 39. Kaskinoro K, Maksimow A, Långsjö J, Aantaa R, Jääskeläinen S, Kaisti K, Särkelä M, Scheinin H. Wide inter-individual variability of bispectral index and spectral entropy at loss of consciousness during increasing concentrations of dexmedetomidine, propofol, and sevoflurane. Br J Anaesth 2011;107:573–80 40. Metzner J, Kent CD, Slimp J, Tredway T, Domino KB. Effects of dexmedetomidine on motor evoked potential monitoring during spine surgery. Anesthesiology 2008;109:A243 41. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000;93:382–94
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