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NEUROSURGICAL ANESTHESIA

Remifentanil- and Fentanyl-Based Anesthesia for Intraoperative Monitoring of Somatosensory Evoked Potentials

Satwant K. Samra, MD^*, Eric A. Dy, BS^,*, Kathleen B. Welch, MS, Lisa K. Lovely, REEGEPT, and Gregory P. Graziano, MD

Departments of *Anesthesiology, Biostatistics, Neurology, and Orthopedic Surgery, University of Michigan Health System, Ann Arbor, Michigan

Address correspondence and reprint requests to Satwant K. Samra, MD, Department of Anesthesiology, University of Michigan Health System, 1H247UH, Box 0048, 1500 E. Medical Center Drive, Ann Arbor, MI 48109. Address e-mail to satsam{at}umich.edu

	Abstract

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We sought to compare effects of remifentanil- and fentanyl-based anesthesia on the morphology of somatosensory evoked potentials (SSEPs) and speed of recovery from anesthesia. Forty-one patients undergoing spinal surgery and requiring intraoperative monitoring of SSEPs were randomized into two groups. In Group 1, anesthesia was induced with sodium thiopental and maintained with fentanyl, 50% nitrous oxide in oxygen, and 0.5%–0.75% isoflurane. In Group 2, anesthesia was induced with sodium thiopental and maintained with remifentanil, 50% oxygen in air, and 0.5%–0.75% isoflurane. The variables compared included hemodynamic changes during the induction and intubation, the interval from the end of anesthesia to extubation, intraoperative blood loss and fluid administration, and changes in latency and amplitude of the P37–N45 component of posterior tibial nerve somatosensory evoked potentials and the N20–P24 component of median nerve somatosensory evoked potentials. The two groups were matched for demographics, ASA physical status, and duration of surgery. Hemodynamic profiles after the induction and intubation were similar. There were significant differences between groups in time intervals from the end of anesthesia to extubation (15.3 ± 12.8 vs 5.3 ± 2.3 min; P = 0.0001) and ability to follow verbal commands (14.6 ± 11.9 vs 4.5 ± 2.4 min; P = 0.0001), with the Remifentanil group showing earlier recovery. Variability (coefficient of variation) of P37–N45 latency was greater (0.026 vs 0.014; P = 0.001) in the Fentanyl group.

Implications: Both fentanyl- and remifentanil-based anesthesia are well suited for intraoperative somatosensory evoked potentials monitoring. Remifentanil anesthesia offers the advantage of earlier recovery, which may improve the ability to do a wake-up test if it is needed during surgery.

	Introduction

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In the last two decades, intraoperative monitoring of somatosensory evoked potentials (SSEPs) has been used with increasing frequency. Despite the limitation of this monitoring technique, i.e., the ability to monitor only the sensory pathways, SSEPs monitoring decreases neurologic injury after spinal surgery for scoliosis (1). The reliability of this monitoring is improved if technical, physiologic, and pharmacologic factors influencing the morphology of SSEPs wave forms can be carefully controlled and held constant throughout the monitoring period. Drugs used to induce and maintain general anesthesia are often titrated up and down and significantly affect the morphology of SSEPs wave forms. Although a study of the comparative effects of narcotics and inhaled anesthetics on SSEPs (in the same patient population) has never been published, several separate clinical studies (2–8) have shown that inhaled anesthetics decrease the amplitude of cortical components of SSEPs to a greater extent than the predominantly narcotic-based general anesthesia. However, major concerns in using large doses of narcotics to provide adequate levels of anesthesia (without the use of inhaled anesthetics) have been (a) the risk of intraoperative recall, (b) slow awakening, and (c) postoperative ventilatory depression. Slow awakening is undesirable in patients whose cooperation in assessment of neurological function in the immediate postoperative period is required.

The common anesthetic technique used for patients requiring intraoperative monitoring of SSEPs at our institution is one of balanced anesthesia, combining the use of nitrous oxide (50%) in oxygen, small-dose isoflurane (0.5%–0.75% end tidal), and small-dose (1–2 µg · kg^-1 · h^-1) fentanyl. Remifentanil hydrochloride is a new opioid agonist that has been recently approved for clinical use during general anesthesia and monitored anesthesia care. Remifentanil has a pharmacokinetic profile that ensures a rapid onset of action and rapid clearance and has no accumulation even when used for long surgical procedures (9). Remifentanil therefore offers a distinct potential advantage over fentanyl. Lack of accumulation, even after long periods of infusion, combined with the rate of clearance being independent of the total dose used, suggests that one can use this drug in doses sufficient to maintain adequate analgesia with concomitant use of inhaled anesthetics in very small doses (to prevent intraoperative awareness). Such an anesthetic regimen will potentially eliminate the suppression of amplitude of SSEPs by inhaled anesthetics. This technique theoretically promises to be good for both rapid awakening and minimal effect on morphology of SSEPs wave forms.

The aims of this study were to compare the effects of replacement of fentanyl and nitrous oxide by remifentanil (in a balanced anesthesia paradigm) on the speed of recovery from anesthesia and the morphology of SSEPs wave forms as measured by changes in amplitude and latency over time. The use of nitrous oxide in one group (and not in the other) will lead to the groups not being strictly comparable. However, these data were collected to evaluate the use of an alternate anesthetic technique (remifentanil and small-dose isoflurane in oxygen) in comparison with a currently used anesthetic technique and to compare the speed of recovery, ability to follow verbal commands, and changes in morphology of SSEPs.

	Methods

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Institutional approval of the study protocol was obtained. Forty-one adult patients (18 men and 23 women) who were scheduled to undergo elective vertebral column surgery with intraoperative monitoring of SSEPs were recruited to participate in this study, and informed consent was obtained. All patients were premedicated with 1–3 mg midazolam before the induction of anesthesia. Obese patients (body weight > 30% of normal population) were excluded. Study subjects were randomized (with a random numbers table) into two groups on the basis of anesthetic management, as described below.

Group 1 (Fentanyl)
Anesthesia was induced with IV sodium thiopental (3–7 mg/kg), and intubation was facilitated by use of a muscle relaxant. Fentanyl 2–3 µg/kg was given IV as a single dose before intubation if this was deemed necessary by the anesthesiologist. Anesthesia was maintained with nitrous oxide (50%) and isoflurane (0.5%–0.75% end tidal) supplemented by nondepolarizing muscle relaxants and fentanyl infusion (1–2 µg · kg^-1 · h^-1). Fentanyl infusion was stopped 45 min before the anticipated end of surgery. Toward the end of surgery, the isoflurane concentration was titrated down per the anesthesiologist’s usual practice and stopped at the beginning of skin closure. Nitrous oxide was stopped at the end of surgery (last skin suture). Times of stopping all medications were noted.

Group 2 (Remifentanil)
Anesthesia was induced with sodium thiopental (3–7 mg) IV, and remifentanil infusion at a rate of 0.5 µg · kg^-1 · min^-1 IV was started simultaneously. Endotracheal intubation was facilitated with a muscle relaxant. Remifentanil infusion was titrated according to blood pressure (BP) response. Anesthesia was maintained with 50% oxygen in air and isoflurane 0.5%–0.75% (end-tidal concentration) supplemented by muscle relaxants and remifentanil infusion. At the beginning of skin closure, after monitoring of SSEPs had been completed, isoflurane was replaced by 50% nitrous oxide. Both nitrous oxide inhalation and remifentanil infusion were stopped at the end of surgery (last skin suture). Approximately 15 min before the end of surgery, a 1–2 µg/kg dose of fentanyl IV was given for postoperative analgesia.

The site of operation determined the SSEPs modality recorded. SSEPs were recorded in response to stimulation of the median nerve (cervical spine surgery), the posterior tibial nerve (lumbar spine surgery), or both (thoracic spine surgery). Upper-extremity SSEPs were recorded in 24 patients (fentanyl = 11, remifentanil = 13). Lower-extremity SSEPs alone were recorded in one patient (Fentanyl group), and both upper and lower extremity SSEPs were recorded in the remaining 16 patients (fentanyl = 8, remifentanil = 8). Stimulation and recording variables from SSEPs recordings are listed in Table 1. SSEPs were recorded at the following time points:

1. 1. After the induction of anesthesia and positioning of the patient for surgery (baseline recordings).
   
2. 2. Before surgical manipulation of the spine (second baseline). The time intervals between the first and second baseline were variable, depending on the complexity of the surgical exposure.
   
3. 3. Throughout the period of surgical manipulation. SSEPs were continuously monitored for variable time periods.
   
4. 4. At the end of surgical manipulation during closure of the surgical wound. SSEPs monitoring was discontinued at the beginning of skin closure. Recall that isoflurane was stopped in the Fentanyl group and was replaced by 50% nitrous oxide in the Remifentanil group at this time.
   

All SSEP traces were stored for off-line analyses and measurements of latency and amplitude of N20–P24 and P37–N45. During surgery, only a qualitative, on-line analysis (i.e., a gross abnormality of wave forms in terms of marked and persistent change in latency, amplitude, or both of these components) was used to warn the surgeon of an impending danger of spinal cord ischemia. For the purpose of this research, quantitative data analyses included both changes in absolute latencies and peak-to-peak amplitudes, as well as an assessment of variability over time by calculating the coefficient of variation of N20–P24 and P37–N45 for all recordings. One electroencephalogram technologist (LKL), who was not present during surgery and was blinded to the anesthetic technique, did all off-line quantitative measurements of latency and amplitude.

Numeric data for systemic arterial BP and heart rate (HR) were automatically stored on a floppy disk at 1-min intervals for off-line data analyses. In addition, end-tidal CO₂ and peripheral oxygen saturation were continuously displayed, thus ensuring adequate and constant ventilation and oxygenation at all time points. Changes in BP and HR after the induction (just before intubation) and 2 min after intubation compared with preinduction values were statistically analyzed as a measure of hemodynamic stability during the induction of anesthesia.

During emergence from anesthesia, time intervals from discontinuation of nitrous oxide until the patient’s ability to follow verbal commands and the extubation of the trachea were noted.

Numeric data for latency and amplitude of P37–N45 and N20–P24 of SSEPs, recorded for the entire duration in each patient, were used to calculate the group mean ± SD of P37–N45 and N20–P24. Variability of SSEPs morphology was expressed as coefficient of variation. Comparisons between groups for different variables were done by using an independent sample t-test (if the normality assumption was met) or Wil-coxon’s rank-sum test (if the normality assumption was not met). Demographic data were analyzed with Fisher’s exact test and the t-test for independent samples. P values <0.05 were considered significant.

	Results

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All patients underwent surgical procedures successfully, and none had a new neurological deficit after surgery. Satisfactory SSEPs were recorded in all patients, allowing adequate monitoring at all times. Persistent changes in SSEPs suggestive of impending spinal cord ischemia were observed in one patient in the Remifentanil group, who was undergoing cervical spine fusion. Impingement of the spinal cord by hardware was suspected, and replacement of existing screws with ones of shorter length resulted in an immediate return of SSEPs amplitude toward baseline. Because the change in SSEPs was obviously related to surgical instrumentation and the purpose of this study was to compare the effect of two anesthetic regimens, we chose to exclude this patient’s data from statistical analyses.

Table 2 shows the demographic data for 40 patients. There were no intergroup differences in age, height, weight, or distribution by sex and ASA physical status. Data for hemodynamic and recovery profiles in the two groups are shown in Table 3. Duration of surgery and changes in HR and BP after the induction of anesthesia and intubation in the two groups were similar. There were significant differences between the two groups in recovery from anesthesia. Patients in the Remifentanil group responded to verbal commands earlier (mean time = 4.5 ± 2.4 vs 14.6 ± 11.9 min, P < 0.0001), and the interval from discontinuation of anesthesia to tracheal extubation was also shorter in the Remifentanil group (mean time = 5.3 ± 2.3 vs 15.3 ± 12.8 min, P < 0.0001). Table 4 shows the numeric values for latencies and amplitudes of various SSEPs components in the two groups. Amplitude of P37–N45 was better preserved in the Remifentanil group, but this difference achieved statistical significance only in the left extremity traces. Variability in SSEPs wave form morphology was determined by calculating coefficients of variation for latency and amplitude of P37–N45 and N20–P24 of SSEPs (Table 5). Variability in amplitude and latency of N20–P24 was similar between the two groups. Coefficient of variation for latency of P37–N45 was more in the Fentanyl group. The coefficient of variation for the amplitude of P37–N45 was also more in the Fentanyl group, although this difference achieved statistical significance only on the left extremity (Table 5).

	Discussion

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We realize that a difference of 10 minutes’ quicker recovery is achieved with the increased cost of using remifentanil (US$52.32 for remifentanil versus US$0.64 for fentanyl for an average case in this study). However, we want to emphasize that in one case in which SSEPs suggested impending spinal cord ischemia and the surgeon requested an immediate wake-up test, it was reassuring that a remifentanil infusion was being used and that the wake-up within five to seven minutes was predicted. It is very difficult to assign a monetary value to this comfort level of anesthesiologists and surgeons, which could play an important role in the outcome of the surgical procedure. The mean duration of anesthesia in our study was 254 minutes for the Remifentanil group and 224 minutes for the Fentanyl group. This 30-minute difference was not statistically significant, but the difference between time intervals from discontinuation of anesthesia to following the verbal commands between the two groups was significant, with the Remifentanil group showing quicker recovery. It is reasonable to hypothesize that for the more complicated cases of longer duration, the difference in recovery from anesthesia (as judged by patient’s ability to follow verbal commands, thus making a clinical neurological examination possible) between the two groups may be even more remarkable because of the lack of accumulation of remifentanil. Our findings of shorter time intervals from the end of anesthesia to following verbal commands and extubation of the trachea are similar to the results of a recent multicenter study (10) that compared the use of fentanyl and remifentanil in patients having craniotomies. We did not find a difference between the groups when the hemodynamic response to the induction of anesthesia and intubation were compared. This finding is similar to the observations made by Guy et al. (11), who compared hemodynamic responses after the induction of anesthesia with remifentanil and fentanyl in patients undergoing craniotomy.

Satisfactory SSEPs monitoring was feasible with both anesthetic techniques. A qualitative on-line analysis used by an electroencephalogram/evoked potentials technician showed no significant, persistent changes in latency or amplitude of various components of SSEPs in 40 of 41 patients. In one patient (from the Remifentanil group) a decreased amplitude of SSEPs was attributed to a surgical cause.

We conclude that both remifentanil and fentanyl infusion during balanced anesthesia allow satisfactory monitoring of SSEPs. Remifentanil infusion offers the advantage of quicker recovery from anesthesia and less variability in SSEPs morphology. This may be of particular advantage in long surgical procedures, in which accumulation of fentanyl becomes a concern. However, these advantages need to be balanced against an increased cost and the vigilant control of postoperative pain relief that will be required for patients in the Remifentanil group.

	Acknowledgments

 
Supported by a grant (investigator-initiated protocol) from Glaxo Wellcome to Dr. Samra.

	Footnotes

 
Presented at the 74th annual meeting of the International Anesthesia Research Society, Honolulu, HI, March 11–14, 2000.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999