The effects of propofol and isoflurane on intraoperative motor evoked potentials during spinal cord tumour removal surgery - A prospective randomised trial.

BACKGROUND AND AIMS: Transcranial electrical stimulation (TES) elicited intraoperative motor evoked potentials (iMEPs), are suppressed by most anaesthetic agents. This prospective randomised study was carried out to compare the effects of Isoflurane and Propofol on iMEPs during surgery for spinal cord tumours.
METHODS: A total of 110 patients were randomly divided into two groups. In group P, anaesthesia was maintained with intravenous propofol (6.6 ± 1.5 mg/kg/hr) and in group I anaesthesia was maintained with isoflurane (0.8 ± 0.1% minimal alveolar concentration (MAC). An Oxygen- air mixture (FiO2-0.3) was used in both groups. TES-iMEPs were recorded from tibialis anterior, quadriceps, soleus and external anal sphincter muscles in 60 of 90 patients. Statistical analysis was performed with Pearson correlation and Paired 't' tests.
RESULTS: Successful baseline iMEPs were recorded in 74% of patients in Group P and in 50% of patients in Group I. Age and duration of symptoms influenced the elicitation of baseline iMEPs under isoflurane (r = -0.71, -0.66 respectively, P < 0.01) as compared to propofol (r = -0.60, -0.50 respectively, P < 0.01). The mean stimulus strength required to elicit the baseline iMEPs were lesser in propofol (205 ± 55Volts) as compared to isoflurane (274 ± 60 Volts). Suppression of the iMEP responses was less under propofol (7.3%) as compared to isoflurane anaesthesia (11.3%) in patients with no preoperative neurological deficits.
CONCLUSION: iMEPs are better maintained under propofol anaesthesia (6-8 mg/kg/hr) when compared with isoflurane (0.7-0.9 MAC). in patients undergoing surgery for excision of spinal cord tumours.

INTRODUCTION

Transcranial electrical stimulation is commonly used to elicit intraoperative motor evoked potentials (iMEPs) under general anaesthesia. It is well known that iMEPs are highly suppressed by most of the anaesthetic agents in a dose-dependent manner.[12] iMEPs are affected by most of the inhalational, intravenous anaesthetics and muscle relaxants at clinically relevant doses. Inhalational anaesthetic agents inhibit the pyramidal activation of spinal motor neurons at the level of the ventral horn[3] or the cortical internuncial synapses.[4] Most of the intravenous agents suppress the activation of the alpha motor neurons at the spinal grey matter.[5] Hence, to achieve meaningful iMEPs, it is not only important to standardise the technical aspect of stimulation of neural structures and recordings of the iMEPs, but also to standardise the anaesthetic techniques.

In general, the choice and management of anaesthesia for spinal cord surgeries is of significant interest to neurophysiologist and anaesthesiologists. However, there were no appropriate randomised studies on anaesthetic choices and their effect on iMEPs.[6] Pelosi et al., 2001, compared inhalational (isoflurane) versus intravenous anaesthetics (propofol) intraoperatively, using nitrous oxide.[7] It is well known that nitrous oxide reduces iMEPs in a dose-dependent manner.[8] Animal studies have shown that suppressive effect of nitrous oxide on motor evoked potentials can be reversed by train stimulation under ketamine/fentanyl anaesthesia, but not with additional doses of propofol.[9] To date, there seem to be no guidelines regarding ideal anaesthetic conditions for monitoring iMEPs in spinal cord tumour removal surgeries.

The primary endpoint of this randomised trial was to compare the suppressive effects of propofol (intravenous anaesthesia) and isoflurane (inhalational anaesthesia) on baseline iMEPs without nitrous oxide under partial neuromuscular blockade[101112] in patients undergoing for spinal cord tumours removal surgery. The secondary endpoint was to assess the possible preoperative clinical factors that could have an influence on eliciting baseline iMEP responses under these two anaesthetic regimes.

METHODS

The study was approved by the Institutional Review Board. Patients age ranged between 18-69 years, with an American Society of Anesthesiologists physical status I-III were included in the study. Informed written consent was obtained, in their native language, from all patients who were willing to participate in the study. Patients undergoing surgery for spinal cord tumour removal with clinical Nurick's grade (0-5) and MRC (Medical Research Council) grade (0-5) were included in the study. Patients with a history of seizures, head injury, or stroke, and those younger than 10 years of age (due to safety concerns) were excluded from the study. Neurological examination was done by the independent neurosurgeon who was blinded to this study at least 12 hr prior to the study. Functional status of all patients was recorded using Nurick grading system and individual muscle power was graded based on the MRC grading system. All the patients underwent a pre-anaesthetic assessment by the anaesthesiologist the day before the surgery. On the day of surgery, all patients received 10 mg of diazepam orally, as premedication 2 h before induction of anaesthesia. In the operating room, an intravenous access and standard anaesthetic monitoring was established. Anaesthesia was induced with fentanyl (2 μg/kg) and sodium thiopentone till loss of eye lash reflex. Injection vecuronium 0.1 mg/kg was used to facilitate the tracheal intubation. Patients were randomised into two groups to receive propofol or isoflurane for maintenance of anaesthesia on the basis of a computer-generated randomization table. In group I, anaesthesia was maintained with isoflurane and air in 30% oxygen (FiO2-0.3).

In Group P anaesthesia was maintained with an intravenous (IV) infusion of propofol and air in 30% oxygen (FiO2-0.3). An IV infusion of vecuronium was administered to maintain a Train-of-Four (TOF) of 2 or 3 twitches. Analgesia was maintained by bolus doses of fentanyl (1 μg/kg) administered every hourly. To maintain the appropriate depth of general anaesthesia during the course of surgery, we maintained the bispectral index between 50 and 60 in both propofol and isoflurane groups. The BIS was maintained by titrating the infusion of propofol or isoflurane concentrations. The minimum alveolar concentration of isoflurane or the dose of propofol being administered was recorded every 15 minutes. This was later averaged for the total duration of the anaesthesia.

iMEPs were recorded using Viking IV or Endeavour (Nicolet Biomedical Inc, Madison, Wisconsin, USA), linked to a D185 (Digitimer Ltd., Welwyn Garden City, UK) for transcranial electrical stimulation (TES). Transcranial electrical stimulation was delivered by placing an anode (2 cm silver disc) at Cz' (1 cm behind the Cz position) and a cathode at FpZ (electroencephalogram 10–20 electrode system). A train of 5 pulses (50 μsec/pulse width duration) with a 2-msec time interval between them was termed a 'sweep'. Five such sweeps at 0.7 Hz were delivered and responses were averaged. Stimulus intensity was started at 100V and gradually increased in steps of 10V. Stimulus intensity was increased until all muscles undergoing monitoring were recruited or until the surgeon warned of patient movement or perceptible paraspinal muscle movement was noticed on the monitor linked to the operating microscope. Stimulus strength was then reduced until no movement was observed.

A baseline iMEPs was obtained by TES immediately after intubation. iMEPs recording was continued intraoperatively till the completion of the skin closure. The following muscles were monitored bilaterally during surgery: Tibialis anterior, Soleus, Quadriceps and External anal sphincter. Compound muscle action potentials (CMAPs) were recorded from the belly of these muscles (except external anal sphincter) with a pair (5 cm apart) of uninsulated subcutaneous needle electrodes. The time base was set at 100 ms and the filter bandpass was 10Hz–1kHz.

The preoperative and postoperative neurological assessment using MRC and Nurick [Table 1] gradings were done by an independent investigator who was blinded to this study. The sample size was calculated based on a study by Pelosi et al.[7] on the basis of the percentage of successful iMEP recordings obtained during surgery. The successful iMEP recordings are defined as the total number of muscles intended to monitor and the actual number of muscle iMEP recordings obtained successfully after the stimulation under the two anaesthetic conditions. We used Pearson correlation to calculate the sample size. With an alpha error of 5%, beta error of 20%, and power of 80%, the sample size for each group was calculated to 34. Pearson correlation method was used to assess the direct relationship between anaesthetics effect on preoperative clinical factors in obtaining baseline iMEP recordings in both propofol and isoflurane groups. Student's independent sample t-test was used to assess the inter-group comparisons. Paired 't' test was used to analyse the changes in stimulus strength from preoperative to postoperative period. For all tests, a P < 0.05 was considered as statistical significant.

Table 1

Patient preoperative neurological assessment using Medical Research Council (MRC) and Nurick grading systems

MRC Grading	Nurick Grading
Grade 5: Muscle contracts normally against full resistance	Grade 5: Chair bound or bedridden.
Grade 4: Muscle strength is reduced but muscle contraction can still move joint against resistance.	Grade 4: Able to walk with someone else’s help or the aid of a frame.
Grade 3: Muscle strength is further reduced such that the joint can be moved only against gravity with the examiner’s resistance completely removed.	Grade 3: Difficulty in walking that prevents full-time employment.
Grade 2: Muscle can move only if the resistance of gravity is removed.	Grade 2: Slight difficulty walking that does not prevent full-time employment.
Grade 1: Only a trace or flicker of movement is seen or felt in the muscle or fasciculation are observed in the muscle.	Grade 1: Signs of spinal cord involvement, but no difficulty walking.
Grade 0: No movement is observed.	Grade 0: Root signs and symptoms. No evidence of spinal cord involvement

RESULTS

A total of 110 patients in the OPD services between March 2004 and June 2007 were initially included in the study [Figure 1]. Twenty of 110 patients were discontinued for participation and dropped out from the study. Ninety patients were eligible and enrolled in the study. Fifteen out of 90 screened patients with a history of seizures, head injury, stroke or younger than 10 years of age (due to safety concerns) were excluded from the study. Six of 90 did not consent to participate. Finally, a total of 69 patients were randomised (by a computer-generated randomisation list using SAS software -SAS Institute, Cary, NC) and allocated to receive either propofol (Group-P, n = 34) or isoflurane (Group-I, n = 35) anaesthesia. Of the 69 patients, 21 patients (Group-P = 9 patients and Group-I = 12 patients) had no preoperative neurological deficits. Intraoperative adverse events in the form of multiple episodes of bradycardia and/or hypotension was seen in 9 patients (n = 4 in Group-P, n = 5 in Group-I, respectively). These patients were excluded from the final analysis. Finally, 60 patients (30 patients from each group) were included for the analysis. The average dose of propofol used to maintain anaesthesia was 6.6 ± 1.5 mg/kg/h and the average MAC of isoflurane used to maintain anaesthesia was 0.8 ± 0.1. The demographic data and the anaesthetic parameters of the patients between two groups are summarised in Table 2. Under propofol anaesthesia, successful baseline iMEPs were recorded in 74% of the cases as compared to 50% of the cases under isoflurane anaesthesia. Patient characteristics, stimulus strength and details of muscles from which motor evoked potentials were recorded in the two study groups are summarised in Table 3.

Figure 1

Consort flow of diagram explaining the phases of a parallel randomised trial of two groups (inclusive of enrolment, intervention allocation, follow-up and data analysis)

Table 2

Demographic data and the anaesthetic parameters of the patients between two groups

	Group P	Group I
No. of Patients	30	30
Age in years (Mean±SD)	38±13	40±15
Anaesthetic Parameters:(Mean±SD)
Thiopentone (induction dose in mg)	171±32	220±16
Maintenance of Anaesthesia	Propofol 6.6±1.5 mg/kg/h	Endtidal Isoflurane concentration 0.75±0.1%
Total Fentanyl bolus (µg)	186±13	164±10
Vecuronium infusion (mg/kg/h)	0.042±0.006 (0.030-0.065)	0.040±0.005

P – Propofol, I – Isoflurane

Table 3

Patient characteristics, stimulus strength and details of muscles from which Motor evoked potentials were recorded in the two study groups

Variables	Group P (n=34)	Group I (n=35)
Patients excluded from the final analysis due to adverse intraoperative events (bradycardia/hypotension)	4	5
Patients included for the final analysis	30	30
Patients with no preoperative neurological deficit	9	12
Stimulus Strength (Volts) (Mean±SD)	205±55**	274±60
Stimulus strength changes from Preoperative to Postoperative period (%)	7.3	11.3
No. of muscles recorded in neurologically intact patients (%)	64/72 (89)*	62/96 (65)
Proportion of Muscles with Baseline Responses (%)
Number of muscles recorded (Bilaterally)	178/240 (74)	120/240 (50)
Quadriceps	35/60 (58)	20/60 (33)
Tibialis Anterior	51/60 (85)	38/60 (63)
Soleus	49/60 (82)	35/60 (58)
External Anal Sphincter	43/60 (72)	27/60 (45)

*Indicates statistically significant at the level of P<0.05 and **at the level of P<0.01

We also studied the effect of anaesthesia on baseline iMEPs in patients with no known neurological deficits (Nurick's Grade-0) in the preoperative period. Our result shows that 89% of the baseline iMEP responses could be recorded under propofol (n = 9 patients) and 65% under isoflurane (n = 12 patients) anaesthesia in such patients with no known neurological deficits. The analysis shows that there was a significant difference (P < 0.05) between the groups and isoflurane has more suppressive effect in obtaining the baseline iMEP responses.

In the present study, we found that the preoperative clinical factors such as neurologic status, age and duration of symptoms have an effect on elicitation of baseline iMEPs responses and it depends on the type of anaesthesia. Preoperative neurologic status has a strong influence on elicitation of baseline iMEP responses in both anaesthetic regimens. It was also noted in our study, that regardless of preoperative neurological deficits (in both Nurick and MRC gradings), as compared to propofol anaesthesia, isoflurane has more suppressive effect in obtaining the successful baseline iMEPs responses [Figure 2a and 2b].

Figure 2

(a): Correlation between Nuricks grade and percentage of iMEP recordings obtained from various muscles in patients receiving proprofol and isoflurane anaesthesia. X axis-Percentage of iMEP recordings; Y axis-Nuricks grade. (b): Correlation between MRC grade and percentage of iMEP recordings obtained from various muscles in patients receiving proprofol and isoflurane anaesthesia. X axis-Percentage of iMEP recordings; Y axis-MRC grade

Age has a significant influence on elicitation of baseline iMEP responses in both propofol and isoflurane anaesthesia. Our result showed that there is an inverse relationship between the patient's age and baseline iMEP responses. As compared to propofol (r = −0.60, P < 0.01), significant higher degree of negative correlation was found in patients under isoflurane anaesthesia (r = −0.71, P < 0.01) [Figure 3a]. The correlation trend line shows that isoflurane has a more profound effect after 30 years in age. In our study, patients over 40 years under propofol anaesthesia, iMEP responses could be recorded in 60% of the muscles while under isoflurane group responses it could be recorded only about 40% of the muscles.

Figure 3

(a): Influence of age on elicitation of baseline iMEPs recordings from monitored muscles under propofol and isoflurane anaesthesia. (b): Influence of duration of symptoms on elicitation of baseline iMEPs recordings from various muscles in patients receiving proprofol and isoflurane anaesthesia

Similar to age, duration of symptoms also has a significant influence on elicitation of baseline iMEP responses under both anaesthetic regimens. Increase in patient's duration of symptoms decreases the elicitation of baseline iMEP responses in both propofol and isoflurane anaesthesia. The analysis shows that, propofol has significant but lesser degree of negative correlation (r = −0.50, P < 0.01) as compared to isoflurane anaesthesia (r = −0.66, P < 0.01) [Figure 3b]. The correlation trend line shows that in patients with >12 months of duration of symptoms, 42% iMEP responses could be recorded under propofol anaesthesia while it is lesser under isoflurane (35%) anaesthesia.

The effects of anaesthesia on stimulus strength to elicit baseline iMEPs were analysed in our study. In propofol anaesthesia, lesser stimulus strength required to elicit baseline iMEPs (mean ± SD = 205 ± 55Volts) as compared to isoflurane (mean ± SD = 274 ± 60Volts) anaesthesia (P < 0.01).

Pre-surgery to post-surgery increment in stimulus strength is considered to be an anaesthetic fading effect. In the present study, the analysis was done to see the stimulus strength increment (potential fading) was caused by propofol and isoflurane anaesthesia. The results show that increase in stimulus strength from preoperative to postoperative stage was present under both anaesthetic regimens. However, the effects [Figure 4a] were less pronounced under propofol anaesthesia (from 205 ± 55V to 220 ± 50V) as compared to isoflurane anaesthesia (from 274 ± 60V to 305 ± 61V, P < 0.01).

Figure 4

(a): Mean stimulus strength to maintain iMEP recordings (anaesthesia fading effect) from preoperative to postoperative (up to the final surgical suture) periods in patients receiving propofol and isoflurane anaesthesia. (b): Line diagram depicting the need for incremental trend of stimulus strength with the increase in duration of anaesthesia. The need for increase in mean stimulus strength is less in patients receiving propofol anaesthesia than in patients receiving isoflurane anaesthesia

In patients with no preoperative neurological deficits, preoperative to postoperative increase in stimulus strength (percentage changes) to maintain the baseline iMEPs were also analysed in the intraoperative period. Less number of patients required an increase in stimulus strength under propofol anaesthesia (n = 9; 7.3%) compared to isoflurane anaesthesia. (n = 12; 11.3%). It was observed that an increase in the duration of the maintenance phase of anaesthesia correlated with a gradual suppression of baseline iMEPs amplitudes (fading effect). An, iatrogenic injury results in sudden drop in iMEP amplitudes but not a gradual drop in amplitudes. A gradual drop in amplitude was more evident under isoflurane anaesthesia than under propofol [Figure 4b].

DISCUSSION

Halogenated inhalational agents and intravenous anaesthetics cause a significant dose-dependent depression of iMEPs and lower the success rate of intraoperative neurophysiological monitoring (IONM) in patients with no preoperative neurological deficits.[13] In our prospective randomised study, the overall success rate in obtaining baseline iMEP recordings were higher under propofol anaesthesia as compared to isoflurane with respect to individual monitored muscles. Though our study population with no preoperative neurological deficits was small, we obtained a significantly higher success rate in baseline iMEP recordings under propofol (n = 9) anaesthesia as compared to isoflurane (n = 12) anaesthesia. Studies on patients with preoperative neurologic deficits in spinal cord surgery suggest that it could affect the success rate in obtaining baseline iMEPs.[1415] These findings support our hypothesis that preoperative neurologic deficits and anaesthesia has higher synergistic suppressive effect in obtaining baseline iMEPs in spinal cord tumour removal surgery. The higher success rate in eliciting baseline iMEP recordings with less suppressive effect (in patients with or without neurological deficits) was observed in our study under propofol anaesthesia when compared to isoflurane anaesthesia. This suggests that isoflurane may influence and suppresses the pyramidal cell activation of spinal motor neurons to elicit iMEPs as compared to propofol that suppresses the alpha motor neuron at the spinal grey matter.[5]

In our experience, we found that preoperative clinical factors like age and duration of symptoms played a significant role in predicting the postoperative outcome. Similar results were observed by Velayutham et al. with intraoperative MEP changes in patients undergoing surgery for thoracic spinal cord tumours.[16] Aging is associated with decrease in nervous tissue mass, neuronal density and concentrations of various neurotransmitters.[1718] In general, nervous system is the virtual target for all the anaesthetic drugs and its maintenance is more complex in nature with age related changes in maturation and degeneration. This throws a greater challenge to an anaesthetist to manage the drugs intraoperatively with dynamic function of the central and peripheral nervous systems especially in neurosurgical procedures. Literature also suggests that, anaesthetic agents are more sensitive with increase in age and require smaller doses for the similar clinical effect with longer duration of action.[17] In our study, this synergistic effect of decrease in nervous tissue mass and longer duration of drug action with increase in age (>35 years) may reduce the acquirement of baseline iMEPs. These combined suppressive effects on baseline iMEP responses were higher under isoflurane as compared to propofol anaesthesia in patients with >35 years of age. We observed that patients with >35 years in age require higher stimulus strength (mean of 265 ± 35 Volts) as compared to patients with <35 years in age which requires lesser (mean of 240 ± 20 Volts). However, these differences between the two groups were not statistically significant.

Previous studies have shown that the duration of symptoms may affect the severity of neurological deficits and favourable functional outcome after spinal surgeries.[19] In our study we observed that the duration of symptoms plays a vital role in obtaining baseline iMEPs. We were able to record the baseline iMEPs up to 75% if the patients had a duration of symptoms (myelopathy) <10 months in both propofol and isoflurane group. Besides, propofol anaesthesia seems to be better to monitor at least 50% of the muscles in patients with >10 months in myelopathy as compared to isoflurane anaesthesia. Pelosi et al.,[7] compared propofol and isoflurane anaesthesia in orthopaedic spinal cord procedures and found that propofol requires lesser stimulus intensity to elicit iMEP recordings when compared to isoflurane anaesthesia. In our study, we also observed that propofol requires lesser stimulus intensity to elicit baseline iMEP recordings as compared to isoflurane anaesthesia. This also could be due to the direct depression of pyramidal cell excitability of spinal motor neurons by isoflurane anaesthesia.

Studies on the deterioration of iMEP responses over the duration of surgery under anaesthesia have been observed in various spinal surgical procedures.[1202122] Identification of anaesthetic fading effect is essential when interpreting the changes in iMEP response to avoid false positive findings. We measured the stimulus strength with respect to elicitation and maintenance of iMEPs at multiple time points rather than a baseline and final point to better determine the kinetics of anaesthetic fade. The progressive suppression of iMEP responses (due to fading effect) was observed in patients with no preoperative neurological deficits in both the anaesthetic regimens in our study. The fading kinetics was lesser under propofol as compared to isoflurane anaesthesia.

In summary, interpretation of iMEPs requires a profound knowledge of neurophysiology, comprehension of the surgical procedure and an understanding of the effects that general anaesthesia and physiological changes may have on signal quality. In our study, successful baseline iMEP recordings are highly associated with preoperative functional grade, motor power and clinical factors like age and duration of symptoms in patients undergoing surgery for excision of spinal cord tumours. As compared to propofol anaesthesia, isoflurane has more impact on these preoperative functional and clinical factors to elicit baseline iMEPs. Anaesthetic fading effect is also significantly lesser with propofol anaesthesia. Isoflurane has a higher fading effect when compared to propofol. Our findings could help in assessing the effect of preoperative clinical factors along with appropriate anaesthetic regimen on the feasibility of obtaining iMEPs in the lower limbs of patients undergoing surgery for the spinal cord tumours.

Limitation and further scope of the study: In the present study, we were not able to quantify the synergistic effect of both age and duration of symptoms to acquire baseline iMEPs with respect to the anaesthesia technique used intraoperatively. We assessed only muscle iMEPs but no D-wave monitoring was done to check the integrity of the corticospinal tract. D-waves may be least affected by the anaesthetic used.[23] A larger prospective study may be conducted to evaluate the synergistic effects of age and duration of symptoms on iMEPs. This would pave the direction to determine and maintain the appropriate dose of anaesthetics in patients with particular age and duration of symptoms to obtain successful baseline iMEPs. Besides, this would also help and minimise intraoperative variations in iMEPs. This may help in a better interpretation of iMEPs and prediction of the postoperative neurological deficits in patients undergoing surgery for the excision of spinal cord tumours.

CONCLUSION

Preoperative neurological deficits, age, duration of symptoms and fading effects highly influenced the elicitation and maintaining of the iMEPs by isoflurane anaesthesia when compared with the propofol anaesthesia in patients undergoing surgery for the excision of spinal cord tumours.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.