British Journal of Anaesthesia 94 (2): (2005) doi: /bja/aei003 Advance Access publication October 29, 2004

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1 British Journal of Anaesthesia 94 (2): (2005) doi: /bja/aei003 Advance Access publication October 29, 2004 CLINICAL PRACTICE Effects of isoflurane and propofol on cortical somatosensory evoked potentials during comparable depth of anaesthesia as guided by bispectral index E. H. C. Liu 1, H. K. Wong 2, C. P. Chia 1, H. J. Lim 1, Z. Y. Chen 2 and T. L. Lee 1 * 1 Department of Anaesthesia and 2 Department of Orthopaedic Surgery, National University Hospital, 5 Lower Kent Ridge Road, Singapore *Corresponding author. analeetl@nus.edu.sg Background. The aim of this study was to determine if propofol caused less suppression of cortical somatosensory evoked potentials (SSEPs) during spine surgery compared with isoflurane during comparable depth of anaesthesia as guided by bispectral index (BIS) measurements. Methods. This was a randomized controlled trial of propofol and isoflurane involving 60 patients undergoing elective spine surgery. BIS monitoring was used to guide a consistent and comparable depth of anaesthesia, the index was maintained at between 40 and 50 during anaesthesia. The cortical SSEP P40-N50 peak-to-peak amplitude and latency time to the P40 peak were measured before induction of anaesthesia, after induction of anaesthesia, at the start of skin incision, at the start of pedicle screw insertion and at the start of rod insertion, by a neurophysiologist blinded to drug allocation. Results. Both propofol and isoflurane decreased SSEP amplitude and increased latency during the course of anaesthesia. After achieving a comparable depth of anaesthesia, the SSEP amplitude was significantly lower with isoflurane, 1.5 (1.0) vs 2.4 (1.4) mv (P=0.005). Latency was significantly longer with isoflurane, 39.5 (3.9) vs 37.3 (3.1) ms (P=0.024). Isoflurane was associated with greater variability of SSEP amplitude during the course of anaesthesia and surgery, coefficient of variation 35.4 (18.0) vs 21.2 (10.2)% (P=0.008). Conclusions. Propofol anaesthesia caused less suppression of the cortical SSEP, with better preservation of SSEP amplitude, and less variability at an equivalent depth of anaesthesia. Br J Anaesth 2005; 94: Keywords: anaesthetics i.v., propofol; anaesthetics volatile, isoflurane; monitoring, bispectral index; monitoring, somatosensory evoked potentials Accepted for publication: September 17, 2004 Intraoperative monitoring of cortical somatosensory evoked potentials (SSEP) during spine instrumentation surgery has been shown to reduce the incidence of neurological complications, and has superseded the Stagnara wakeup test. 12 SSEP monitoring is now regarded as the standard of care, and is less affected by technical difficulties than motor evoked potential monitoring. 2 Despite its advantages over wakeup tests, retrospective studies have reported the sensitivity of SSEP to be as low as 92%, and specificity as low as 85.3%. 13 There are no clear definitions of SSEP changes, which are considered to be indicative of spinal cord dysfunction. Empirically, a 50% reduction in amplitude and 10% increase in latency have been used as indicators for many years. 124 Most anaesthetic drugs can cause decreases in amplitude and increases in latency of SSEP waveforms. This can cause problems in interpretation, including failure to diagnose spinal cord injury and take corrective action, as well as unwarranted diagnosis of injury and unnecessary treatment. Therefore, anaesthetists have a role in preserving the quality of SSEP monitoring with their choice of techniques and drugs. In a review, observational studies had reported that inhalational anaesthetics caused more depression of the SSEP than i.v. anaesthetics. However, few prospective studies have been done and these have shown conflicting results. 5 It is also difficult to assess results where high doses of anaesthetics are used without sensitive monitors of anaesthetic depth. # The Board of Management and Trustees of the British Journal of Anaesthesia 2004

2 Liu et al. We compared the effects on the SSEP of isoflurane and propofol, the main inhalation and i.v. anaesthetics used in our institution, in a randomized trial. We aimed to determine which anaesthetic enabled identifiable and consistent cortical SSEP waveforms to be obtained for intraoperative spinal cord monitoring. We used bispectral index (BIS) monitoring of the hypnotic effects of anaesthetics to standardize the depth of anaesthesia. We measured the SSEP in the awake patients before induction of anaesthesia, to enable a full comparison of the changes from the awake to the anaesthetized state. We did not use nitrous oxide to prevent its confounding effects. Methods We obtained Institutional Review Board approval and written informed consent from all patients involved in this study. Where patients were under the age of 21 yr, we obtained consent from both the patient and a parent. Patients having elective spine surgery, in whom SSEP monitoring was to be used routinely, were recruited. The patients who had no neurological deficits, and were of ASA I and II physiological status, were included. Patients who had sensory or motor deficits preoperatively, significant cardiovascular, respiratory or renal disease, a history of alcoholism, or who were on treatment with sedative or psychiatric drugs were excluded from the trial. The investigators were unaware of drug allocation at the time of recruitment. After recruitment, patients were allocated in blocks of 10, in a ratio of 1:1, to receive isoflurane or propofol anaesthesia using a block randomization table. We commenced BIS monitoring in all patients before the induction of anaesthesia, using a BIS XP monitor (Aspect Medical Systems Inc., Natick, MA, USA). For patients in the isoflurane group, anaesthesia was induced with propofol 2 mg kg 1 and alfentanil 10 mg kg 1. Anaesthesia was maintained with isoflurane delivered in an air oxygen mixture of carrier gas. The concentration of isoflurane was adjusted to maintain the BIS between 40 and 50 during surgery. For patients in the propofol group, anaesthesia was induced with propofol 2 mg kg 1 and alfentanil 10 mg kg 1. Anaesthesia was maintained with a propofol infusion. The infusion was commenced at 10 mg kg 1 h 1 and then adjusted to maintain the BIS between 40 and 50 during surgery. Muscle relaxation was achieved with atracurium, to maintain one twitch on train-of-four monitoring. The trachea was intubated in every patient and positive pressure ventilation was adjusted to maintain normocapnia. I.V. morphine was used for intraoperative analgesia in all patients. We monitored arterial pressure, heart rate, nasopharyngeal temperature, urine output, and end tidal carbon dioxide concentration in all the patients. We used a warm air blower to warm the patients legs, maintained the room temperature at 23 C, used warm i.v. fluids, and used low fresh gas flows and a heat moisture exchanger to try to reduce the extent of patient hypothermia. Where required, we induced hypotension with esmolol and phentolamine to reduce bleeding during surgical exposure, but still maintained the mean arterial pressure above 60 mm Hg in all patients. We did not increase the dosage of anaesthesia to induce hypotension. SSEPs were recorded using a Medelec Synergy system (Oxford Instruments Medical Limited, Old Woking, Surrey, UK). SSEP measurements were obtained by stimulating the posterior tibial nerve bilaterally. For this study, SSEP measurements obtained from stimulating the right tibial nerve were used for statistical analysis. Stimulus intensity was set at 2 ma above the threshold, which elicited contraction of the foot muscles, and was kept constant in each patient. Stimulus currents were ma in our patients, using a duration of 200 ms and frequency of 3.11 Hz. We used an analysis time of 100 ms and averaged 200 sweeps. The cortical SSEP was recorded using the Cz Fz montage in the international system of EEG electrode placement. We used a filter band pass setting of 20 Hz to 20 khz. We used the nomenclature of posterior tibial SSEPs described by Nuwer. 1 We assessed the latency of the SSEP by measuring the time to the P40 peak. We assessed the amplitude of the SSEP by measuring the peak-to-peak voltage difference between the P40 and N50 peaks. All the SSEP measurements were taken by one neurophysiologist (Z.Y.C.) who was blinded to the group allocation of patients. The SSEP was firstly measured when the patients were awake, before the induction of anaesthesia. The SSEP was continuously monitored during surgery and anaesthesia. Our primary outcome measures were the SSEP latency and amplitude during the maintenance phase of anaesthesia but before the commencement of surgery. This was at least 20 min after induction of anaesthesia, when the depth of anaesthesia was steady and the BIS readings had shown minimal variation (less than 10) for at least 10 min. This was to ensure that any residual effect of the propofol used to induce anaesthesia would be minimal. The patients were supine with limbs and neck in neutral position. They were normotensive, normocapnic, and normothermic at this time. We used ephedrine to maintain the mean arterial pressure within 20% of the awake baseline blood pressure during this period. Secondary outcomes were the SSEP measurements at the starting times of skin incision, pedicle screw insertion (where screws were used), and rod insertion (where rods were used). Patients were withdrawn from the trial if the SSEP amplitude decreased to less than 0.3 mv, as such deterioration can make interpretation of the SSEP difficult. We used independent sample t-tests, corrected for unequal variances, for the comparison of absolute amplitude and latency of the right posterior tibial SSEP during anaesthesia but before the commencement of surgery. We considered a 0.6 mv difference in amplitude as clinically worthwhile, and estimated the standard deviation (SD) tobe 0.8 mv from pilot data. At least 27 patients were required in each group for 80% power to detect such a difference. t-tests were used to compare the magnitude of change of amplitude 194

3 Isoflurane and propofol effects on the SSEP and latency, from pre-induction to after induction of anaesthesia. Two-way repeated measures ANOVA was used to assess the drug allocation effect over time during anaesthesia. We also assessed the coefficient of variation for each patient for amplitude and latency over time, to compare the variation in SSEP parameters over time between groups. (Coefficient=SD/mean 100% of the four measurements taken during anaesthesia, calculated for individual patients.) Data are presented as means (SD). Results Sixty patients were recruited. The patients in the two groups were similar in age, gender, weight, and operation type (Table 1). The SSEP measurements are detailed in Table 2. The SSEP latency and amplitude were not significantly different before induction of anaesthesia between the two groups. The latency was significantly longer and the amplitude significantly smaller in the isoflurane group after induction of anaesthesia, and at the times of incision, screw insertion, and rod insertion (Table 2). In comparing the Table 1 Patients characteristics. Values are mean (SD) [range] or numbers Isoflurane (n=30) Propofol (n=30) Age (yr) 28 (20) [12 73] 25 (18) [12 62] Sex (M/F) 6/24 6/24 ASA status (I/II) 24/6 26/4 Weight (kg) 54 (15) 50 (16) Height (m) 1.61 (0.06) 1.61 (0.07) BMI (kg m 2 ) 19.5 (3.9) 19.2 (4.8) Operation type (n) Scoliosis posterior instrumentation Scoliosis thoracoscopic 3 5 instrumentation Transforaminal lumbar 7 5 interbody fusion Disc replacement 3 3 Anterior lumbar interbody fusion 1 0 Cervical instrumentation 1 1 SSEP changes from the awake to the anaesthetized states, isoflurane caused larger decreases in amplitude than propofol, 0.4 (0.9) vs +0.1 (1.1) mv (P=0.05), and larger increases in latency, +1.9 (1.9) vs +0.7 (1.6) ms (P=0.02). In repeated measures ANOVA and comparisons of the coefficients of variation, we analysed the measurements taken after induction of anaesthesia and during surgery, to assess if the drug effect continued during the course of anaesthesia and surgery. Pre-induction measurements were not included. In repeated measures ANOVA, isoflurane caused a greater decrease in amplitude (P<0.001) and a greater increase in latency (P=0.001) during the course of surgery. Time also had a significant effect on the amplitude (P<0.001), with amplitude decreasing during the time course of anaesthesia and surgery, and on latency (P<0.001), with latency increasing during the time course. Isoflurane caused significantly greater variation in the amplitude over the time course, coefficient of variation 35.4 (18.0) vs 21.2 (10.2) (P=0.008). The difference in coefficients of variation in latency was not statistically significant, isoflurane 5.4 (3.2)% and propofol 4.0 (2.2)% (P=0.07). In two patients in the isoflurane group, the amplitude decreased to less than 0.3 mv after surgery had commenced but before the insertion of pedicle screws. These patients were withdrawn from the trial, blinding was removed, and we changed the anaesthetic to propofol for these two patients. This resulted in improvement of the amplitude to more than 0.3 mv. No patient had SSEP abnormalities that necessitated wakeup tests or surgical correction. No patient had neurological deficits postoperatively. Discussion At an equivalent depth of anaesthesia guided by BIS monitoring, isoflurane caused a greater decrease in the amplitude and an increase in the latency of the SSEP than propofol. Preservation of the SSEP amplitude at critical time points during surgery was much better with propofol, and did not Table 2 Somatosensory evoked potential results. Values are mean (SD). *P<0.05 comparing isoflurane and propofol. a Temperature awake measured with ear thermometer, temperatures during anaesthesia measured with nasopharyngeal probe Awake, before induction of anaesthesia After induction of anaesthesia At skin incision At start of pedicle screw insertion At start of spinal rod insertion Amplitude (mv) Isoflurane 2.0 (0.7) 1.5 (1.0) 1.2 (0.8) 0.9 (0.6) 1.0 (0.2) Propofol 2.3 (1.7) 2.4 (1.4)* 2.3 (1.4)* 2.0 (1.2)* 2.0 (1.1)* Latency (ms) Isoflurane 37.5 (4.3) 39.5 (3.9) 40.8 (4.2) 42.0 (4.6) 43.4 (5.4) Propofol 36.6 (3.6) 37.3 (3.1)* 38.3 (2.9)* 39.6 (3.3)* 39.9 (3.4)* Bispectral index Isoflurane 96.4 (3.3) 45.2 (2.7) 42.0 (5.8) 39.4 (11.0) 44.3 (7.7) Propofol 94.9 (3.8) 43.9 (2.7) 39.8 (5.3) 41.6 (8.1) 39.3 (5.2) Temperature ( C) a Isoflurane 36.5 (0.2) 36.4 (0.4) 36.0 (0.7) 36.2 (3.1) 35.2 (1.1) Propofol 36.4 (0.3) 36.1 (0.8) 35.6 (0.7) 35.1 (0.8) 34.7 (1.1) MAP (mm Hg) Isoflurane 87.7 (15.3) 76.2 (11.7) 73.9 (15.1) 63.1 (18.0) 68.7 (10.8) Propofol 88.4 (15.2) 78.3 (12.4) 79.2 (10.6) 74.4 (14.4) 72.7 (9.8) 195

4 Liu et al. decrease below 0.3 mv in any patient receiving propofol. Although both increases in latency and decreases in amplitude indicate danger to the spinal cord, we used a decrease in amplitude as the primary criteria, and aimed to maintain the amplitude above 0.3 mv. We emphasized amplitude preservation to enable a more accurate interpretation of the latency. Secondly, amplitude variability is also negatively correlated with amplitude itself, and preservation of amplitude will reduce confounding from baseline variability and electrical noise. 56 This study also showed that the SSEP parameters changed during the course of surgery with both propofol and isoflurane. Comparing later measurements with those taken at the start of surgery may be inappropriate. New baseline measurements may need to be taken during the course of surgery, before potentially dangerous manoeuvres, even during propofol anaesthesia. We attempted to standardize the conditions during the primary comparison after induction of anaesthesia. We avoided increasing the dose of anaesthesia when induced hypotension was required, and used vasodilators and betablockers instead. We maintained the mean arterial pressure above 60 mm Hg to reduce the risk of ischaemic injury, and to prevent SSEP changes as a result of excessive hypotension. While there were no significant differences in the arterial pressure and temperature at the measurement times during anaesthesia, it was not possible to exclude the effects of confounding by these and other factors in the comparisons. Decreases in temperature have been reported to increase latency by 3% and decrease amplitude by 7% per degree Celsius decrease in an animal study. 7 Although we were unable to completely standardize all factors, this trial reflects the conditions during surgical practice. However, this trial s conclusions may not be applicable to patients with preoperative neurological abnormalities. As anaesthetics have a greater effect on synaptic transmission than on axonal conduction, polysynaptic cortical SSEPs are affected much more than subcortical evoked potentials. The mechanism explaining the varying extent of SSEP depression of different anaesthetics is still unknown. Earlier work on isoflurane suggested that SSEP monitoring was satisfactory with isoflurane concentrations of up to 1.0 minimum alveolar concentration (MAC), even though isoflurane could cause attenuation of the SSEP At higher doses, isoflurane can cause a morphologic change in the SSEP, including contraction of early cortical waveforms into a simple monophasic wave and very marked attenuation of late cortical waveforms. Although waveform morphology may be better preserved during propofol anaesthesia, propofol has been reported to cause a temporary increase in amplitude after induction, which can affect subsequent interpretation of amplitude measurements. Propofol can also cause marked increases in latency A sequential observational study comparing isoflurane and propofol found greater suppression of the posterior tibial nerve SSEP with isoflurane, but no differences in the median nerve SSEPs. 16 One randomized study in children undergoing scoliosis surgery comparing propofol and sevoflurane concluded that propofol and sevoflurane had similar effects on the posterior tibial nerve SSEP. 17 One difficulty in interpretation is that nitrous oxide had been used in these studies. Nitrous oxide itself can cause substantial reduction in cortical SSEP amplitude, and it also potentiates the effects of inhalation anaesthetics A recent study comparing sevoflurane and propofol in adults undergoing elective shoulder surgery found less SSEP depression with propofol. 20 It is possible that differences in anaesthetic depth contributed to these different results. Our study complements these earlier works by taking pre-anaesthetic and intraoperative measurements to enable a complete comparison during normal surgical practice, while maintaining a consistent depth of anaesthesia. We found that with BIS guidance, we often used lower concentrations of isoflurane, and higher infusion rates of propofolthan we would have in the absence of BIS monitoring. BIS monitoring has been shown to reduce anaesthetic usage and recovery time. This can facilitate wakeup tests if these are needed to confirm problems detected by SSEP monitoring. A limitation is that BIS monitors the effects of drugs on the EEG, and that comparable EEG effects may not equate with comparable responses to surgical stimulation. Although the MAC concept is commonly used to guide dosage, it is based on an all or none motor response to a noxious stimulus in the absence of neuromuscular blocking agents. BIS had the advantages of providing continuous and scalar assessment of depth of hypnosis. In this study, even with equivalent BIS values, there cannot be absolute certainty about equivalent depth of anaesthesia between isoflurane and propofol, although BIS monitoring will reduce the risk of significant differences. Although propofol had less effect on the SSEP in our study, we notice that there may be great variability in propofol requirement, and greater haemodynamic changes with propofol. Propofol may not be similarly superior to all other inhalational anaesthetic drugs. When neuromuscular block was avoided to facilitate motor evoked potential monitoring in other patients, we found that more patients moved in response to surgical stimulus during propofol anaesthesia compared with isoflurane anaesthesia. This may be because propofol has a different effect on the spinal cord than isoflurane, even when BIS is used to guide dosing to achieve similar depth of hypnosis. One consideration is that more time may be required before a wakeup test can be carried out with propofol compared with inhalation anaesthetics. 17 In conclusion, the cortical SSEP waveforms were better preserved with propofol compared with isoflurane, facilitating interpretation of the SSEP. We recommend that propofol anaesthesia rather than isoflurane anaesthesia be used when intraoperative SSEP monitoring is required, but only after considering the risks to the individual patient and the experience of the anaesthetist. 196

5 Isoflurane and propofol effects on the SSEP Acknowledgements We thank Aspect Medical Systems International B.V., KG Leiden, The Netherlands, for providing the Bispectral index monitors for this study. References 1 Nuwer MR, Dawson EG, Carlson LG, Kanim LE, Sherman JE. Somatosensory evoked potential spinal cord monitoring reduces neurologic deficits after scoliosis surgery: results of a large multicenter survey. Electroencephalogr Clin Neurophysiol 1995; 96: Raw DA, Beattie JK, Hunter JM. Anaesthesia for spinal surgery in adults. Br J Anaesth 2003; 91: Papastefanou SL, Henderson LM, Smith NJ, Hamilton A, Webb JK. Surface electrode somatosensory-evoked potentials in spinal surgery: implications for indications and practice. Spine 2000; 25: Brown RH, Nash CL jr, Berilla JA, Amaddio MD. Cortical evoked potential monitoring. A system for intraoperative monitoring of spinal cord function. Spine 1984; 9: Banoub M, Tetzlaff JE, Schubert A. Pharmacologic and physiologic influences affecting sensory evoked potentials: implications for perioperative monitoring. Anesthesiology 2003; 99: Kalkman CJ, ten Brink SA, Been HD, Bovill JG. Variability of somatosensory cortical evoked potentials during spinal surgery. Effects of anesthetic technique and high-pass digital filtering. Spine 1991; 16: Jou IM. Effects of core body temperature on changes in spinal somatosensory-evoked potential in acute spinal cord compression injury: an experimental study in the rat. Spine 2000; 25: Peterson DO, Drummond JC, Todd MM. Effects of halothane, enflurane, isoflurane, and nitrous oxide on somatosensory evoked potentials in humans. Anesthesiology 1986; 65: Pathak KS, Amaddio MD, Scoles PV, Shaffer JW, Mackay W. Effects of halothane, enflurane, and isoflurane in nitrous oxide on multilevel somatosensory evoked potentials. Anesthesiology 1989; 70: Lam AM, Sharar SR, Mayberg TS, Eng CC. Isoflurane compared with nitrous oxide anaesthesia for intraoperative monitoring of somatosensory-evoked potentials. Can J Anaesth 1994; 41: Porkkala T, Kaukinen S, Hakkinen V, Jantti V. Median nerve somatosensory evoked potentials during isoflurane anaesthesia. Can J Anaesth 1997; 44: Porkkala T, Jantti V, Kaukinen S, Hakkinen V. Somatosensory evoked potentials during isoflurane anaesthesia. Acta Anaesthesiol Scand 1994; 38: Scheepstra GL, de Lange JJ, Booij LH, Ros HH. Median nerve evoked potentials during propofol anaesthesia. Br J Anaesth 1989; 62: Borrissov B, Langeron O, Lille F, et al. Combination of propofolsufentanil on somatosensory evoked potentials in surgery of the spine. Ann Fr Anesth Reanim 1995; 14: Kalkman CJ, Traast H, Zuurmond WW, Bovill JG. Differential effects of propofol and nitrous oxide on posterior tibial nerve somatosensory cortical evoked potentials during alfentanil anaesthesia. Br J Anaesth 1991; 66: Taniguchi M, Nadstawek J, Pechstein U, Schramm J. Total intravenous anesthesia for improvement of intraoperative monitoring of somatosensory evoked potentials during aneurysm surgery. Neurosurgery 1992; 31: Ku AS, Hu Y, Irwin MG, et al. Effect of sevoflurane/nitrous oxide versus propofol anaesthesia on somatosensory evoked potential monitoring of the spinal cord during surgery to correct scoliosis. Br J Anaesth 2002; 88: Wolfe DE, Drummond JC. Differential effects of isoflurane/ nitrous oxide on posterior tibial somatosensory evoked responses of cortical and subcortical origin. Anesth Analg 1988; 67: Langeron O, Vivien B, Paqueron X, et al. Effects of propofol, propofol nitrous oxide and midazolam on cortical somatosensory evoked potentials during sufentanil anaesthesia for major spinal surgery. Br J Anaesth 1999; 82: Boisseau N, Madany M, Staccini P, et al. Comparison of the effects of sevoflurane and propofol on cortical somatosensory evoked potentials. Br J Anaesth 2002; 88: Gan TJ, Glass PS, Windsor A, et al. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology 1997; 87: Song D, Joshi GP, White PF. Titration of volatile anesthetics using bispectral index facilitates recovery after ambulatory anesthesia. Anesthesiology 1997; 87: