Monitoring 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 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–γ-aminobutyric 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 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, placebo-controlled, 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.
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.
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 at any point of the study, an infusion rate of propofol and remifentanil <100 and <0.065 μg/kg/min, respectively, were not allowed. Normothermia was maintained.
Hemodynamic instability defined as (a) arterial hypotension (systolic blood pressure <90 mm Hg), (b) arterial hypertension (systolic blood pressure >140 mm Hg), (c) tachycardia (heart rate > 100 beats/min), and (d) bradycardia (heart rate < 40 beats/min) was treated at the discretion of the anesthesiologist.
After the patient was positioned for the surgery and 4 twitches with train-of-four were obtained using the peripheral nerve stimulator (EZstim II, Life-Tech, Inc., Stafford, TX), the first set of EPs was recorded. With train-of-four <4, reversal of neuromuscular blockade with neostigmine and glycopyrrolate was allowed, if necessary, but was not required in any case. After baseline EPs were obtained, the study drug was ini tiated with an IV bolus during 10 minutes, followed by an infusion. The study drug, which was either normal saline (placebo) or dexmedetomidine solution in normal saline, was prepared by the investigational drug services in the hospital pharmacy. The dose was written on the infusion bag: bolus of 0.9 mL/kg/h for 10 minutes followed by a maintenance infusion of 0.15 mL/kg/h, what equaled for dexmedetomidine a bolus of 0.6 μg/kg and a continuous infusion of 0.6 μg/kg/h.
The study drug discontinuation criteria included (1) decrease of amplitude of SSEP or MEP by >50% from the baseline anytime during the surgery or (2) unsatis factory quality of 2 sets of SSEPs or MEPs during the first 30 minutes.
SSEPs, transcranial electrical MEPs, and VEPs were set up using standard half-inch subcutaneous needles at all stimulation and recording sites. Monitoring was performed by a trained neurophysiology technician or a neurophysiologist.
Tibial and median nerve SSEPs were stimulated at standard locations on the ankle and wrist, respectively. SSEPs were recorded with active electrodes at the lateral scalp (C3′ and C4′ are 2-cm posterior to C3 and C4 location, respectively, of the international 10–20 system) for median nerve and at the midline scalp (Cz′) for tibial nerve. These active leads were referred to Fz. In addition, brainstem level responses were monitored with an Fz-mastoid montage. Peripheral nerve monitoring was done with leads placed at the Erb’s point for median nerve and at abductor hallucis muscle for tibial nerve. The latter response also served to affirm the absence of any neuromuscular blockade. For MEP stimulation, anodal pulses were delivered through electrodes placed at C3 and C4, with polarity switching accomplished via software control. MEPs were recorded with an active electrode placed over the belly of the contralateral thenar and abductor hallucis muscles with a reference over the tendon of the muscle.
A Cadwell Cascade neurophysiologic monitoring system (Cadwell Laboratories, Kennewick, WA) was used for stimulation and recording. For SSEPs and MEPs, filter settings were 30 to 1000 Hz. Analysis time was 50 milliseconds for median nerve stimulation and 100 milliseconds for tibial stimulation. SSEPs were averages of 300 sweeps, and MEPs were responses to a single train of stimuli. Tibial and median nerves were stimulated using a 0.2-millisecond duration pulse at an intensity of 50 and 25 mAmps, respectively. MEPs were stimulated using a train of 4 to 8 pulses with an interstimulus interval of 2 milliseconds and an intensity of between 150 and 400 V. SSEPs were monitored at computer-controlled 10- minute time intervals throughout the procedure. MEPs were manually monitored at 5- to 15-minute intervals and were delayed occasionally to eliminate patient movement during critical portions of the surgical procedure. For the VEPs setup, recording needles were placed at the mid-occiput referred to Fz. For stimulation, flash goggles (Cadwell Laboratories) were placed over the patient’s eyes and secured in position with Tegaderm (3M Health Care, St. Paul, MN) or an umbilical tape strap tied around the head. VEP filter settings were 0.5 to 250 Hz, and stimulation rate was 1.05 Hz. VEPs were averages of 200 sweeps. VEPs were manually monitored at 15- to 20- minute intervals throughout the procedure.
Baseline EPs measures were taken before study drug administration and consisted of 2 to 4 measurements. The baseline evaluation (T0) represented the average of these preadministration runs. After study drug administration, data were taken as often as possible at 15- and 30-minute intervals for safety purposes. Because the data collection of EPs takes a few minutes for each average and that surgical demands varied the timing of EPs, EP data for a given time interval (15, 30, and 60 minutes after drug administration) represent the average of runs from the previous time interval to that specific time interval.
Data collection included baseline patient characteristics (age, sex, ASA physical status, comorbidities, chronic medications), description of surgery, and intraoperative vital signs (heart rate, blood pressure, oxygen saturation, BIS, esophageal temperature) were collected and recorded by the study coordinator at baseline (T0), followed by 15-minute intervals, as well as intraoperative use of all the medications. To evaluate drug effects, the following parameters were used: for SSEPs, the P37 latency (initial positive peak) and N33-P37 amplitude (onset to initial positive peak); for MEPs, maximum peak to peak of the abductor hallucis amplitude; for VEPs, N1 and P1 latencies and N1-P1 amplitudes, where N1 referred to the initial prominent negative peak followed by a prominent positive peak P1. For some subjects, MEPs and VEPs could not be recorded because of technical failure. Where data were missing, they were not imputed and included in the statistical analysis. For VEPs, subject’s data were classified as (a) no response, no measureable response, (b) no consistent response, measureable but not reproducible responses, or (c) measureable and reproducible responses. Only the latter subjects were used for statistical analysis.
For power analysis, we used data from the pilot study. Using these planning data (mean MEP amplitude, 500 μV; SD, 400) to detect a 50% difference in MEPs amplitude (decrease from 500 to 250 μV), which would be clinically significant between placebo and dexmedetomidine, 16 patients per treatment arm (32 total) were required with an effect size of 0.8, and assuming a power of at least 80% and a 2-sided α level of 5%. To account for dropouts and missing data, the sample size was inflated to 20 patients per treatment arm to ensure an adequate number of subjects with complete data for the final analysis.
The primary end point was a difference between dexmedetomidine and placebo groups in change of amplitude and latency in EPs from baseline to T1 (at 60 ± 30 minutes after initiation of study drug) and a secondary end point: from baseline to T2 (at 150 ± 30 minutes after initiation of study drug). T1 was computed as the average of 3 measures taken at 30, 60, and 90 minutes after initiation of the study drug (minimum 1 and maximum 3 measures), averaged for each participant. T2 was computed as the average of measures taken at 120, 150, and 180 minutes after initiation of the study drug (minimum 1 and maximum 3 measures).
The analyses were performed on an intent-to-treat basis. Two-sample Student t test was used to compare change from T0 to T1 (primary end point) and from T0 to T2 (secondary end point) between dexmedetomidine and placebo groups. Baseline patient characteristics were compared between groups with 2-sample Student t test for continuous variables and Student t test with unequal variances or Fisher exact test for categorical variables, as appropriate. Data are reported as mean ± SD (95% confidence interval) or n (%), unless otherwise specified. All P values are 2 sided, and α level of 0.05 was considered statistically significant. The statistical software STATA 11.0 (Stata Corp, College Station, TX) was used for all analyses.
Patient flow and randomization assignment are shown in Figure 1. In the period between September 2006 and March 2010, 145 patients scheduled for elective spine surgery with neurosurgical and orthopedic departments were screened for participation. Data of 40 patients were available for the final analysis: 20 patients in the dexmedetomidine group and 20 patients in the placebo group.
There were no differences between the groups in demographic and surgical characteristics of the study population, besides higher incidence of systemic hypertension in the placebo group (Table 1). Both groups remained hemodynamically stable with the blood pressure and heart rate being within the normal limits (no hypotension or hypertension, tachycardia, or bradycardia), and the remainder of vital signs and doses of maintenance anesthetics and concomitant medications did not differ between the groups (Table 2).
Data of EPs are presented in Figure 2. MEPs were not available in 6 cases: not attempted in 5 patients because of a change of surgical plan and in MEPs were not present at baseline in 1 patient (Table 3). VEPs were not attempted in 4 patients, and in 2 patients, baseline data were not available because of technical failures such as the inability to apply goggles or disconnection from them. Poor-quality VEPs were observed in 9 of 34 cases (26%) with signals either not present (5/34; 17%) or present but not measurable (4/34; 9%). All the VEP data, which were included into final analysis (25 cases), were reviewed by 2 experienced neurophysiologists.
Primary and Secondary End Points
There was no difference in the change from baseline to T1 or to T2 in latency or amplitude of SSEPs, MEPs, and VEPs between dexmedetomidine and placebo groups (Tables 3 and 4). There were no complications in this study, and no subject had study drug discontinued because of decrease in amplitude of MEPs.
This study is the first randomized, placebo-controlled trial to date to evaluate the effect of α-2 agonist dexmedetomidine used as an adjunct to TIVA on SSEPs, MEPs, and VEPs. The main findings of our study indicate that a clinically relevant dose of dexmedetomidine does not adversely affect latencies and amplitudes of SSEPs, MEPs, and VEPs compared with placebo. These findings imply that dexmedetomidine in therapeutic doses is safe and that the drug does not seem to alter EPs when used as a part of TIVA. We also observed that recording of VEPs during spine surgery in any surgical position, including lateral and prone, is only feasible and reliable in 74% of patients.
The major difference between our study and previously published work is that we used a blinded, randomized, placebo-controlled design and a rigorous investigational setting with EPs monitoring during the first 3 hours of dexmedetomidine infusion, along with control of vital signs and the depth of anesthesia. Our data are consistent with previous reports of successful monitoring of intraoperative EPs with a clinically relevant dose of dexmedetomidine as an adjunct to general anesthesia.14 Similar to our findings, Bala et al.14 did not observe changes in the SSEP quality with a plasma concentration of dexmedetomidine >0.3 and 0.6 ng/mL, when it was given in a crossover fashion in 36 adult patients who received desflurane and remifentanil anesthesia. Although because of the interindividual variability of MEPs, the study was inconclusive as to dexmedetomidine’s effect on MEPs, the authors reported achievable EPs in all study subjects with both doses of dexmedetomidine. In contrast, Mahmoud et al.16 reported a suppression of MEPs amplitude in some adolescents with dexmedetomidine given as an adjunct to variable doses of propofol: in 2 of 17 cases with target plasma concentration of dexmedetomidine of 0.4 ng/mL and in 11 of 23 cases with higher target plasma concentration of 0.6 to 0.8 ng/mL. However, an observed plasma concentration was much higher than what was targeted. Similarly, a decrease of amplitude of MEPs (but not SSEPs) after a bolus of 1 μg/kg of dexmedetomidine was reported to occur related to the rapid deepening of anesthesia, as was reflected by the quick decline of the BIS number in another adolescent case series.15 Our study included only adult patients, and the dose of dexmedetomidine we used in our study would lead to an estimated plasma concentration of approximately 1 ng/mL, which could be lower than a real plasma concentration in the study by Mahmoud et al.,16 which was performed with a 1-time point analysis with loading of dexmedetomidine, while we monitored EPs during 3 hours and obtained consistent and reliable recording of MEPs in all study subjects. It is possible that the combination of dexmedetomidine and propofol might have a cumulative suppressing effect on the motor neuron, particularly, if the loading dose of dexmedetomidine >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.
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 the intraoperative environment have been suggested as reasons for failure.20–25,34,35 The use of newly developed light-emitting 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. 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
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 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 temper ature 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.
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.
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.
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.
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