Ir J Med Sci DOI 10.1007/s11845-014-1174-4
ORIGINAL ARTICLE
Effects of different etomidate doses on intraoperative somatosensory-evoked potential monitoring X.-L. Meng • L.-W. Wang • W. Zhao X.-Y. Guo
•
Received: 21 March 2014 / Accepted: 12 July 2014 Ó Royal Academy of Medicine in Ireland 2014
Abstract Background Somatosensory-evoked potentials (SSEPs) are widely used for intraoperative spinal cord monitoring. Although many general anesthetics inhibit SSEPs, etomidate has been reported to boost SSEPs. This clinical study aimed to test whether etomidate doses less than 0.3 mg/kg amplify SSEP monitoring. Methods Patients were divided into four groups: A, B, C, and D. Etomidate doses of 0.1, 0.2, and 0.3 mg/kg were infused into patients in groups A, B, and C, respectively, after baseline SSEPs were obtained. Group D patients were infused with saline. In the subsequent 15 min, the amplitudes and latencies of SSEPs were recorded and compared. Results Etomidate exhibited amplification effects on SSEPs, and this effect increased with dose escalation. The amplitude changes in groups A, B, and C were significantly different (P = 0.002, P = 0.000, and P = 0.000, respectively) from that of group D. The amplitude change was largest in group C and significantly greater than those in groups A and B (P = 0.006, P = 0.000). Latency was not significantly affected (P \ 0.05) by etomidate. Conclusion Small doses of etomidate that were less than 0.3 mg/kg had dose-related amplification effects on SSEP monitoring. Keywords Somatosensory Evoked potentials Anesthesia Etomidate
X.-L. Meng L.-W. Wang W. Zhao X.-Y. Guo (&) Department of Anesthesiology, Peking University Third Hospital, No. 49 Huayuan Road Haidian District, Beijing 100191, China e-mail: [email protected]
Introduction The intraoperative monitoring (IOM) of the spinal cord is widely used in neurosurgery [1, 2]. Somatosensory-evoked potentials (SSEPs) can be used to monitor the function of the sensory nervous system during an operation, and this monitoring is crucial in spinal cord tumor resections [1, 2]. General anesthetics, especially most inhalational anesthetics, can inhibit SSEP monitoring [3–6]. Intravenous anesthetics and opioids such as propofol and remifentanil exhibit reduced inhibitory effects relative to inhalational anesthetics, such that total intravenous anesthesia (TIVA) is preferred in many clinical centers [2, 4]. However, even under TIVA with propofol and remifentanil, eliciting SSEPs remains difficult in some cases, and the optimization of general anesthesia remains a challenge in this field. A special intravenous anesthetic, etomidate, has been reported to facilitate SSEP monitoring [7, 8], but, due to its inhibition of cortisol production, the clinical use of etomidate has been limited [9]. One study has suggested that etomidate has dual effects on evoked potential (EP) monitoring [10]. This assumption indicates that etomidate can amplify EP amplitudes at low doses but depress EP amplitudes at higher doses. This particular study aroused our interest in the effects of different doses of etomidate on SSEPs in neurosurgery. If etomidate can amplify SSEPs at low doses, the drug might be used in clinical applications, and its effects on cortisol production will be attenuated. The present clinical study was designed to evaluate the effects of different small doses of etomidate on SSEP monitoring as well as to explore whether a suitable dose of etomidate can be found for SSEP facilitation.
123
Ir J Med Sci
Materials and methods General information Fifty-one patients with the following characteristics who were scheduled for spinal cord tumor resections were enrolled in the study: American Society of Anesthesiologists physical status, I to II; mean age, 41 years (range 20–65 years); mean weight, 60 kg (range 47–80 kg); and mean height, 165 cm (range 155–185 cm). This study was conducted with approval from the Ethics Committee of Peking University Third Hospital. Written informed consent was obtained from all participants. Anesthesia protocol and maintenance None of the patients was administered premedication before the induction of general anesthesia. When the patients arrived at the operating room, noninvasive blood pressure, pulse oxygen saturation, electrocardiography, and the electroencephalography bispectral index (BIS) were monitored. A catheter was then inserted into a large peripheral vein for the administration of fluids and drugs. Another catheter was inserted into the radial artery to monitor arterial blood pressure (ABP). Anesthesia was induced by the target-controlled infusion (TCI) of propofol (Diprifusor TCI, AstraZeneca, London, UK) and remifentanil (Remifentanil Hydrochloride for Injection, Yichang, China). Both the TCI patterns of propofol and remifentanil were plasma-steered; the starting plasma concentrations were 3 lg/mL and 4 ng/mL, respectively. Cisatracurium 0.1 mg/kg (Cisatracurium Besilate for Injection, Jiangsu, China) was administered to facilitate endotracheal intubation. After endotracheal intubation, mechanical ventilation was begun. The fractional inspired oxygen concentration was 50 % in air. Throughout the operation, the ventilation parameters were adjusted to maintain the arterial CO2 partial pressure between 35 and 45 mmHg. A warming blanket was used to maintain the pharynx temperature between 36 and 37 °C. If necessary, phenylephrine or nicardipine was infused to maintain the ABP change below 20 % of the baseline value (ABP before induction). Fluid administration was guided by central venous pressure and urine output. The depth of anesthesia was kept constant by maintaining the BIS value between 35 and 45.
both sides of the body, depending on the operation sites. After the induction of general anesthesia and before draping, sterile stimulating and recording needle electrodes were positioned in accordance with the international 10–20 system of electrode placement, as described in the American Electroencephalographic Society Guidelines. The cortical response of the lower extremity is called P37, whereas the cortical response of the upper extremity is called N20. The reference electrode was placed over the forehead. The stimulation rate for both the median and posterior tibial nerves was 3.1 Hz, with an artifact rejection level of 50 lV. The stimulating electrodes were placed at C3 and C4. The responses to the SSEPs were displayed on a computer screen in real time and then stored on a hard disk. The P37 latency was measured from the onset of the stimulus to the trough of the P37 potential. The latency of the N20 response was recorded from the onset of the stimulus to the peak of the N20 potential. The amplitudes were measured from the trough to the peak of the P37–N45 complex and from the peak to the trough of the N20–P25 complex. The baseline SSEP was measured when a good signal-tonoise ratio was obtained. The patients were then divided rotationally into four groups: A, B, C, and D. Group D was the control group. Ten patients in this group were infused with 5 mL of saline after the baseline SSEP was obtained. Groups A, B, and C were the treatment groups, and the patients received 0.1, 0.2, or 0.3 mg/kg of etomidate by infusion, respectively, after the baseline SSEP was obtained. The latencies and amplitudes of the SSEPs were then compared with the baseline for 15 min. The changes in latency and amplitude were recorded. In the period during which the effects of etomidate were observed, no important operation procedures could have influenced the SSEPs. Statistical analysis All of the patients were assigned to the four aforementioned groups. The data are presented as mean ± standard deviation. SPSS 17.0 software (IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. A repeated measurements analysis of variance was used to compare the amplitude and latency changes at different time points in the four groups. P values less than 0.05 were considered statistically significant.
Results SSEP monitoring General information The Cadwell neuromonitoring system (Cadwell Cascade Elite; Cadwell Laboratories Inc., Kennewick, WA, USA) was employed. Spinal cord function was monitored by performing recordings in the upper or lower extremities on
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When comparing groups A to D, no significant differences were observed in patient age, body weight, height, or gender (Table 1).
Ir J Med Sci Table 1 General patient information Groups
Gender M
Age (years)
Table 4 Changes in latency in the four groups (A–D)
Body weight (kg)
Height (cm)
Group A
Group B
Group C
Group D
F
Time 1
1.31 ± 1.51
-1.41 ± 1.38
0.77 ± 0.86
1.28 ± 1.50
1.58 ± 2.23
-0.50 ± 2.13
1.88 ± 2.08
2.04 ± 2.07
3.68 ± 4.81
0.46 ± 1.60
1.40 ± 2.06
2.76 ± 2.25
A
7
7
40 (22–60)
60 (45–70)
165 (156–175)
Time 2
B
6
8
39 (22–60)
59 (47–75)
164 (155–175)
Time 3
C
7
6
40 (23–63)
62 (50–80)
165 (160–185)
Time 4
0.86 ± 3.69
-0.27 ± 1.59
0.32 ± 2.09
0.63 ± 3.57
166 (160–180)
Time 5
1.63 ± 2.15
0.32 ± 1.23
1.83 ± 2.59
0.52 ± 2.11
D
5
5
40 (20–65)
63 (49–80)
M male, F female
Table 2 Variables relating to depth of anesthesia and hemodynamic parameters Groups
BIS
MAP (mmHg)
HR (bpm)
T (°C)
A
40–60
75 (60–90)
62 (52–80)
36.0 (35.5–36.7)
B
40–60
75 (63–90)
64 (51–74)
36.3 (36.0–36.8)
C
40–60
74 (64–85)
63 (53–73)
36.4 (35.7–36.8)
D
40–60
75 (67–90)
64 (53–74)
36.4 (35.8–37.1)
BIS bispectral index, MAP mean arterial blood pressure, HR heart rate, T temperature Table 3 Number of positive and negative cases in the three treatment groups
Groups
Positive
Negative
A
10
4
B C
10 10
4 3
Time 6
2.33 ± 7.66
0.26 ± 0.60
0.75 ± 1.58
0.63 ± 3.15
Time 7
0.37 ± 1.69
0.03 ± 1.46
0.54 ± 1.19
0.54 ± 1.43
Time 8
2.29 ± 1.62
0.07 ± 2.19
0.44 ± 1.78
0.28 ± 2.35
Time 9
0.56 ± 2.23
0.67 ± 1.33
0.22 ± 1.90
0.49 ± 2.19
observed in the four groups during the 15-min period after etomidate infusion (Table 4). However, significant changes in amplitude were observed in the comparison of groups A, B, and C with group D (Table 5; Fig. 1). All three treatment groups manifested an SSEP amplification effect. The change in amplitude was significantly higher in group C than in groups A and B (P \ 0.05). The change in amplitude in group C is shown in Fig. 2. The amplification effect of etomidate on SSEPs was dose related, although no significant difference (P = 0.130) was observed between groups A and B.
Discussion Depth of anesthesia and hemodynamic parameters As required by the protocol, the BIS was maintained between 35 and 45 after intubation. The changes in the hemodynamic parameters were maintained at 20 % of the baseline value that was determined the day before the operation (Table 2). SSEPs In the three treatment groups, A, B, and C, the effects of the different doses of etomidate differed. Following etomidate infusion, some cases manifested an SSEP amplification effect (positive), whereas others exhibited no change (negative). The latency and amplitude changes in the positive cases in each group were compared with those of the control group (D). The number of positive and negative cases in each group did not differ significantly (P = 0.753; Table 3). Latency and amplitude In patients who exhibited an amplification effect of etomidate (positive), no significant changes in latency were
SSEP is the earliest form of neurological monitoring that was introduced into the operating room [1–3]. This modality is capable of assessing the integrity of the sensory pathways that traverse the spinal cord in areas at risk for injury. Combined with motor-evoked potentials (MEPs), SSEPs still exert an important influence in neurosurgery [1, 2]. Many general anesthetics can inhibit SSEP and MEP monitoring, while TIVA, consisting of propofol and remifentanil, has been reported to be appropriate for IOM [3, 4, 7]. However, even under TIVA with propofol and remifentanil, eliciting SSEPs and MEPs remains difficult in some cases. Optimizing the anesthesia protocol remains a challenge for anesthesiologists in this field. Etomidate is a special intravenous anesthetic [11]. Despite being a gamma-aminobutyric acid (GABA) receptor agonist like propofol, the effects of etomidate on IOM are significantly different from those of propofol. Etomidate acts on different subtypes of the GABA receptor [11–13], and this may result in changes in the balance of inhibitory and excitatory influences in the central nervous system, thus manifesting different effects on SSEPs and MEPs compared to propofol [13]. The facilitative effects of etomidate on SSEPs have been reported in numerous studies [7, 8].
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Ir J Med Sci Table 5 Changes in SSEP amplitude in the four groups
Group A Time 1
* Significantly different as compared with other values in the same group P \ 0.05 ** Significantly different as compared with other groups P [ 0.05
-0.19 ± 12.40
123
6.35 ± 12.60
Group C
Group D*
15.09 ± 28.39*
3.83 ± 15.15*
Time 2
38.4 ± 12.57*
43.33 ± 9.16*
50.15 ± 31.02*,**
-3.72 ± 15.71*,**
Time 3
37.03 ± 16.42*
41.88 ± 13.43*
59.08 ± 13.06*,**
4.90 ± 17.38*,**
Time 4
31.49 ± 11.24*
43.90 ± 22.51*
53.00 ± 29.02* **
3.44 ± 10.57*,**
Time 5
11.59 ± 23.90
24.44 ± 10.72
31.90 ± 10.24*
1.92 ± 14.84*
,
Time 6
10.33 ± 20.32
23.62 ± 10.09
24.56 ± 15.85
-0.96 ± 13.08*
Time 7
2.12 ± 20.69
11.32 ± 12.98
18.25 ± 20.65
3.67 ± 14.92
Time 8
0.01 ± 19.07
-3.94 ± 28.98
15.25 ± 24.34
2.39 ± 14.70
Time 9
-0.90 ± 18.92
-8.96 ± 27.97
9.29 ± 25.71
9.72 ± 12.14
Fig. 1 SSEP amplitude changes of the four groups
Fig. 2 Amplification of SSEP amplitude after the administration of etomidate at a dose of 0.3 mg/kg
Group B
Most studies on the effects of etomidate on SSEPs were published before propofol was used as a routine induction anesthetic. Thus, etomidate was tested as an induction drug. Etomidate has also been reported to inhibit cortisol production, and it has been shown to depress the function of the adrenal cortex for longer than 24 h, even after a single induction dose [14]. Thus, the rationale for the clinical use of etomidate has been vigorously debated. Nevertheless, no evidence of excess mortality has been associated with the use of etomidate [15]. We believe that, in spinal cord tumor resection surgery or complex spinal deformity correction surgery, patients do not have sepsis. Moreover, corticosteroids are utilized routinely, although their use is controversial [16, 17]. Thus, the use of etomidate in this kind of surgery should not cause significant adverse effects. The results of an animal study by Sloan and Roger have suggested that etomidate has dual effects on MEPs. At lower doses, etomidate will amplify the amplitudes of SSEPs, but, at relatively higher doses, the drug will depress the amplitudes of SSEPs [10]. This finding suggests that
Ir J Med Sci
etomidate could possibly be applied at a low dose to facilitate EP monitoring. Conversely, when used at a low dose, the depressive effects of etomidate on the adrenal cortex might be attenuated. Thus, we were motivated to conduct the current clinical study in order to explore whether a suitable dose of etomidate exists for IOM. We sought to establish whether etomidate could exert an amplification effect at a low dose in a propofol and remifentanil background. The results of our study demonstrated that, in a TIVA background mainly consisting of propofol and remifentanil, etomidate doses less than 0.3 mg/kg did not exhibit dual effects on SSEPs. The amplification effect on SSEP amplitudes increased following dose escalation. We might infer from this finding that the critical dose at which amplification no longer occurs is higher than 0.3 mg/kg. Another phenomenon that was observed in this study was the variability of the etomidate effects. In each treatment group, some cases exhibited no effects, whereas others showed a dose-related amplification of SSEP amplitudes. One explanation might be that, although etomidate can amplify the amplitudes of SSEP, this effect is not strong enough in some cases to overcome its depression by propofol. In clinical practice, to enhance the SSEP amplification effect, etomidate should be infused continuously, such that its total dose will be significantly higher. Considering the possible dose-related adrenal cortical depressive effects, we believe that increasing the etomidate dose to achieve better amplification of SSEPs is impractical. Thus, in order to optimize the anesthesia plan for difficult cases, other medications, such as a2 receptor agonists [18, 19] or NMDA receptor antagonists [20, 21], can be applied as auxiliary treatments. By reducing the amounts of remifentanil and propofol, the inhibition effects might be attenuated.
Conclusion Small doses of etomidate less than 0.3 mg/kg exhibited dose-related amplification effects on SSEP monitoring, but these effects exhibited considerable variability. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Forster MT, Marquardt G, Seifert V et al (2012) Spinal cord tumor surgery–importance of continuous intraoperative neurophysiological monitoring after tumor resection. Spine(Phila Pa 1976) 37:E1001–E1008
2. Deletis V, Sala F (2008) Intraoperative neurophysiological monitoring of the spinal cord during spinal cord and spine surgery: a review focus on the corticospinal tracts. Clin Neurophysiol 119:248–264 3. Pajewski TN, Arlet V, Phillips LH (2007) Current approach on spinal cord monitoring: the point of view of the neurologist, the anesthesiologist and the spine surgeon. Eur Spine J 16:S115– S129 4. Nuwer M (2008) Intraoperative monitoring of neural function. In: Handbook of Clinical neurophysiology. New York, pp 94–126 5. Sloan T, Sloan H, Rogers J (2010) Nitrous oxide and isoflurane are synergistic with respect to amplitude and latency effects on sensory evoked potentials. J Clin Monit Comput 24:113–123 6. Peterson DO, Drummond JC, Todd MM (1986) Effects of halothane, enflurane, isoflurane, and nitrous oxide on somatosensory evoked potentials in humans. Anesthesiology 65:35–40 7. Koht A, Schu¨tz W, Schmidt G et al (1988) Effects of etomidate, midazolam, and thiopental on median nerve somatosensory evoked potentials and the additive effects of fentanyl and nitrous oxide. Anesth Analg 67:435–441 8. Sloan TB, Ronai AK, Toleikis JR et al (1988) Improvement of intraoperative somatosensory evoked potentials by etomidate. Anesth Analg 67:582–585 9. Fengler BT (2008) Should etomidate be used for rapid-sequence intubation induction in critically ill septic patients? Am J Emerg Med 26:229–232 10. Sloan T, Rogers J (2009) Dose and timing effect of etomidate on motor evoked potentials elicited by transcranial electric or magnetic stimulation in the monkey and baboon. J Clin Monit Comput 23:253–261 11. Forman SA (2011) Clinical and molecular pharmacology of etomidate. Anesthesiology 114:695–707 12. Voss LJ, Sleigh JW, Barnard JP et al (2008) The howling cortex: seizures and general anesthetic drugs. Anesth Analg 107:1689–1703 13. Drexler B, Jurd R, Rudolph U et al (2009) Distinct actions of etomidate and propofol at beta3-containing gamma-aminobutyric acid type A receptors. Neuropharmacology 57:446–455 14. Lundy JB, Slane ML, Frizzi JD (2007) Acute adrenal insufficiency after a single dose of etomidate. J Intensive Care Med 22:111–117 15. Ray DC, McKeown DW (2007) Effect of induction agent on vasopressor and steroid use, and outcome in patients withseptic shock. Crit Care 11:R56 16. Aminmansour B, Khalili HA, Ahmadi J et al (2006) Effect of high-dose intravenous dexamethasone on postlumbar discectomy pain. Spine (Phila Pa 1976) 31:2415–2417 17. Markandaya M, Stein DM, Menaker J (2012) Acute treatment options for spinal cord injury. Curr Treat Options Neurol 14(2):175–187 18. Anschel DJ, Aherne A, Soto RG et al (2008) Successful intraoperative spinal cord monitoring during scoliosis surgery using a total intravenous anesthetic regimen including dexmedetomidine. J Clin Neurophysiol 25:56–61 19. Bala E, Sessler DI, Nair DR et al (2008) Motor and somatosensory evoked potentials are well maintained in patients given dexmedetomidine during spine surgery. Anesthesiology 109: 417–425 20. Zaarour C, Engelhardt T, Strantzas S et al (2007) Effect of lowdose ketamine on voltage requirement for transcranial electrical motor evoked potentials in children. Spine (Phila Pa 1976) 32:E627–E630 21. Frei FJ, Ryhult SE, Duitmann E et al (2007) Intraoperative monitoring of motor-evoked potentials in children undergoing spinal surgery. Spine 32:911–917
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ORIGINAL ARTICLE
Effects of different etomidate doses on intraoperative somatosensory-evoked potential monitoring X.-L. Meng • L.-W. Wang • W. Zhao X.-Y. Guo
•
Received: 21 March 2014 / Accepted: 12 July 2014 Ó Royal Academy of Medicine in Ireland 2014
Abstract Background Somatosensory-evoked potentials (SSEPs) are widely used for intraoperative spinal cord monitoring. Although many general anesthetics inhibit SSEPs, etomidate has been reported to boost SSEPs. This clinical study aimed to test whether etomidate doses less than 0.3 mg/kg amplify SSEP monitoring. Methods Patients were divided into four groups: A, B, C, and D. Etomidate doses of 0.1, 0.2, and 0.3 mg/kg were infused into patients in groups A, B, and C, respectively, after baseline SSEPs were obtained. Group D patients were infused with saline. In the subsequent 15 min, the amplitudes and latencies of SSEPs were recorded and compared. Results Etomidate exhibited amplification effects on SSEPs, and this effect increased with dose escalation. The amplitude changes in groups A, B, and C were significantly different (P = 0.002, P = 0.000, and P = 0.000, respectively) from that of group D. The amplitude change was largest in group C and significantly greater than those in groups A and B (P = 0.006, P = 0.000). Latency was not significantly affected (P \ 0.05) by etomidate. Conclusion Small doses of etomidate that were less than 0.3 mg/kg had dose-related amplification effects on SSEP monitoring. Keywords Somatosensory Evoked potentials Anesthesia Etomidate
X.-L. Meng L.-W. Wang W. Zhao X.-Y. Guo (&) Department of Anesthesiology, Peking University Third Hospital, No. 49 Huayuan Road Haidian District, Beijing 100191, China e-mail: [email protected]
Introduction The intraoperative monitoring (IOM) of the spinal cord is widely used in neurosurgery [1, 2]. Somatosensory-evoked potentials (SSEPs) can be used to monitor the function of the sensory nervous system during an operation, and this monitoring is crucial in spinal cord tumor resections [1, 2]. General anesthetics, especially most inhalational anesthetics, can inhibit SSEP monitoring [3–6]. Intravenous anesthetics and opioids such as propofol and remifentanil exhibit reduced inhibitory effects relative to inhalational anesthetics, such that total intravenous anesthesia (TIVA) is preferred in many clinical centers [2, 4]. However, even under TIVA with propofol and remifentanil, eliciting SSEPs remains difficult in some cases, and the optimization of general anesthesia remains a challenge in this field. A special intravenous anesthetic, etomidate, has been reported to facilitate SSEP monitoring [7, 8], but, due to its inhibition of cortisol production, the clinical use of etomidate has been limited [9]. One study has suggested that etomidate has dual effects on evoked potential (EP) monitoring [10]. This assumption indicates that etomidate can amplify EP amplitudes at low doses but depress EP amplitudes at higher doses. This particular study aroused our interest in the effects of different doses of etomidate on SSEPs in neurosurgery. If etomidate can amplify SSEPs at low doses, the drug might be used in clinical applications, and its effects on cortisol production will be attenuated. The present clinical study was designed to evaluate the effects of different small doses of etomidate on SSEP monitoring as well as to explore whether a suitable dose of etomidate can be found for SSEP facilitation.
123
Ir J Med Sci
Materials and methods General information Fifty-one patients with the following characteristics who were scheduled for spinal cord tumor resections were enrolled in the study: American Society of Anesthesiologists physical status, I to II; mean age, 41 years (range 20–65 years); mean weight, 60 kg (range 47–80 kg); and mean height, 165 cm (range 155–185 cm). This study was conducted with approval from the Ethics Committee of Peking University Third Hospital. Written informed consent was obtained from all participants. Anesthesia protocol and maintenance None of the patients was administered premedication before the induction of general anesthesia. When the patients arrived at the operating room, noninvasive blood pressure, pulse oxygen saturation, electrocardiography, and the electroencephalography bispectral index (BIS) were monitored. A catheter was then inserted into a large peripheral vein for the administration of fluids and drugs. Another catheter was inserted into the radial artery to monitor arterial blood pressure (ABP). Anesthesia was induced by the target-controlled infusion (TCI) of propofol (Diprifusor TCI, AstraZeneca, London, UK) and remifentanil (Remifentanil Hydrochloride for Injection, Yichang, China). Both the TCI patterns of propofol and remifentanil were plasma-steered; the starting plasma concentrations were 3 lg/mL and 4 ng/mL, respectively. Cisatracurium 0.1 mg/kg (Cisatracurium Besilate for Injection, Jiangsu, China) was administered to facilitate endotracheal intubation. After endotracheal intubation, mechanical ventilation was begun. The fractional inspired oxygen concentration was 50 % in air. Throughout the operation, the ventilation parameters were adjusted to maintain the arterial CO2 partial pressure between 35 and 45 mmHg. A warming blanket was used to maintain the pharynx temperature between 36 and 37 °C. If necessary, phenylephrine or nicardipine was infused to maintain the ABP change below 20 % of the baseline value (ABP before induction). Fluid administration was guided by central venous pressure and urine output. The depth of anesthesia was kept constant by maintaining the BIS value between 35 and 45.
both sides of the body, depending on the operation sites. After the induction of general anesthesia and before draping, sterile stimulating and recording needle electrodes were positioned in accordance with the international 10–20 system of electrode placement, as described in the American Electroencephalographic Society Guidelines. The cortical response of the lower extremity is called P37, whereas the cortical response of the upper extremity is called N20. The reference electrode was placed over the forehead. The stimulation rate for both the median and posterior tibial nerves was 3.1 Hz, with an artifact rejection level of 50 lV. The stimulating electrodes were placed at C3 and C4. The responses to the SSEPs were displayed on a computer screen in real time and then stored on a hard disk. The P37 latency was measured from the onset of the stimulus to the trough of the P37 potential. The latency of the N20 response was recorded from the onset of the stimulus to the peak of the N20 potential. The amplitudes were measured from the trough to the peak of the P37–N45 complex and from the peak to the trough of the N20–P25 complex. The baseline SSEP was measured when a good signal-tonoise ratio was obtained. The patients were then divided rotationally into four groups: A, B, C, and D. Group D was the control group. Ten patients in this group were infused with 5 mL of saline after the baseline SSEP was obtained. Groups A, B, and C were the treatment groups, and the patients received 0.1, 0.2, or 0.3 mg/kg of etomidate by infusion, respectively, after the baseline SSEP was obtained. The latencies and amplitudes of the SSEPs were then compared with the baseline for 15 min. The changes in latency and amplitude were recorded. In the period during which the effects of etomidate were observed, no important operation procedures could have influenced the SSEPs. Statistical analysis All of the patients were assigned to the four aforementioned groups. The data are presented as mean ± standard deviation. SPSS 17.0 software (IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. A repeated measurements analysis of variance was used to compare the amplitude and latency changes at different time points in the four groups. P values less than 0.05 were considered statistically significant.
Results SSEP monitoring General information The Cadwell neuromonitoring system (Cadwell Cascade Elite; Cadwell Laboratories Inc., Kennewick, WA, USA) was employed. Spinal cord function was monitored by performing recordings in the upper or lower extremities on
123
When comparing groups A to D, no significant differences were observed in patient age, body weight, height, or gender (Table 1).
Ir J Med Sci Table 1 General patient information Groups
Gender M
Age (years)
Table 4 Changes in latency in the four groups (A–D)
Body weight (kg)
Height (cm)
Group A
Group B
Group C
Group D
F
Time 1
1.31 ± 1.51
-1.41 ± 1.38
0.77 ± 0.86
1.28 ± 1.50
1.58 ± 2.23
-0.50 ± 2.13
1.88 ± 2.08
2.04 ± 2.07
3.68 ± 4.81
0.46 ± 1.60
1.40 ± 2.06
2.76 ± 2.25
A
7
7
40 (22–60)
60 (45–70)
165 (156–175)
Time 2
B
6
8
39 (22–60)
59 (47–75)
164 (155–175)
Time 3
C
7
6
40 (23–63)
62 (50–80)
165 (160–185)
Time 4
0.86 ± 3.69
-0.27 ± 1.59
0.32 ± 2.09
0.63 ± 3.57
166 (160–180)
Time 5
1.63 ± 2.15
0.32 ± 1.23
1.83 ± 2.59
0.52 ± 2.11
D
5
5
40 (20–65)
63 (49–80)
M male, F female
Table 2 Variables relating to depth of anesthesia and hemodynamic parameters Groups
BIS
MAP (mmHg)
HR (bpm)
T (°C)
A
40–60
75 (60–90)
62 (52–80)
36.0 (35.5–36.7)
B
40–60
75 (63–90)
64 (51–74)
36.3 (36.0–36.8)
C
40–60
74 (64–85)
63 (53–73)
36.4 (35.7–36.8)
D
40–60
75 (67–90)
64 (53–74)
36.4 (35.8–37.1)
BIS bispectral index, MAP mean arterial blood pressure, HR heart rate, T temperature Table 3 Number of positive and negative cases in the three treatment groups
Groups
Positive
Negative
A
10
4
B C
10 10
4 3
Time 6
2.33 ± 7.66
0.26 ± 0.60
0.75 ± 1.58
0.63 ± 3.15
Time 7
0.37 ± 1.69
0.03 ± 1.46
0.54 ± 1.19
0.54 ± 1.43
Time 8
2.29 ± 1.62
0.07 ± 2.19
0.44 ± 1.78
0.28 ± 2.35
Time 9
0.56 ± 2.23
0.67 ± 1.33
0.22 ± 1.90
0.49 ± 2.19
observed in the four groups during the 15-min period after etomidate infusion (Table 4). However, significant changes in amplitude were observed in the comparison of groups A, B, and C with group D (Table 5; Fig. 1). All three treatment groups manifested an SSEP amplification effect. The change in amplitude was significantly higher in group C than in groups A and B (P \ 0.05). The change in amplitude in group C is shown in Fig. 2. The amplification effect of etomidate on SSEPs was dose related, although no significant difference (P = 0.130) was observed between groups A and B.
Discussion Depth of anesthesia and hemodynamic parameters As required by the protocol, the BIS was maintained between 35 and 45 after intubation. The changes in the hemodynamic parameters were maintained at 20 % of the baseline value that was determined the day before the operation (Table 2). SSEPs In the three treatment groups, A, B, and C, the effects of the different doses of etomidate differed. Following etomidate infusion, some cases manifested an SSEP amplification effect (positive), whereas others exhibited no change (negative). The latency and amplitude changes in the positive cases in each group were compared with those of the control group (D). The number of positive and negative cases in each group did not differ significantly (P = 0.753; Table 3). Latency and amplitude In patients who exhibited an amplification effect of etomidate (positive), no significant changes in latency were
SSEP is the earliest form of neurological monitoring that was introduced into the operating room [1–3]. This modality is capable of assessing the integrity of the sensory pathways that traverse the spinal cord in areas at risk for injury. Combined with motor-evoked potentials (MEPs), SSEPs still exert an important influence in neurosurgery [1, 2]. Many general anesthetics can inhibit SSEP and MEP monitoring, while TIVA, consisting of propofol and remifentanil, has been reported to be appropriate for IOM [3, 4, 7]. However, even under TIVA with propofol and remifentanil, eliciting SSEPs and MEPs remains difficult in some cases. Optimizing the anesthesia protocol remains a challenge for anesthesiologists in this field. Etomidate is a special intravenous anesthetic [11]. Despite being a gamma-aminobutyric acid (GABA) receptor agonist like propofol, the effects of etomidate on IOM are significantly different from those of propofol. Etomidate acts on different subtypes of the GABA receptor [11–13], and this may result in changes in the balance of inhibitory and excitatory influences in the central nervous system, thus manifesting different effects on SSEPs and MEPs compared to propofol [13]. The facilitative effects of etomidate on SSEPs have been reported in numerous studies [7, 8].
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Ir J Med Sci Table 5 Changes in SSEP amplitude in the four groups
Group A Time 1
* Significantly different as compared with other values in the same group P \ 0.05 ** Significantly different as compared with other groups P [ 0.05
-0.19 ± 12.40
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6.35 ± 12.60
Group C
Group D*
15.09 ± 28.39*
3.83 ± 15.15*
Time 2
38.4 ± 12.57*
43.33 ± 9.16*
50.15 ± 31.02*,**
-3.72 ± 15.71*,**
Time 3
37.03 ± 16.42*
41.88 ± 13.43*
59.08 ± 13.06*,**
4.90 ± 17.38*,**
Time 4
31.49 ± 11.24*
43.90 ± 22.51*
53.00 ± 29.02* **
3.44 ± 10.57*,**
Time 5
11.59 ± 23.90
24.44 ± 10.72
31.90 ± 10.24*
1.92 ± 14.84*
,
Time 6
10.33 ± 20.32
23.62 ± 10.09
24.56 ± 15.85
-0.96 ± 13.08*
Time 7
2.12 ± 20.69
11.32 ± 12.98
18.25 ± 20.65
3.67 ± 14.92
Time 8
0.01 ± 19.07
-3.94 ± 28.98
15.25 ± 24.34
2.39 ± 14.70
Time 9
-0.90 ± 18.92
-8.96 ± 27.97
9.29 ± 25.71
9.72 ± 12.14
Fig. 1 SSEP amplitude changes of the four groups
Fig. 2 Amplification of SSEP amplitude after the administration of etomidate at a dose of 0.3 mg/kg
Group B
Most studies on the effects of etomidate on SSEPs were published before propofol was used as a routine induction anesthetic. Thus, etomidate was tested as an induction drug. Etomidate has also been reported to inhibit cortisol production, and it has been shown to depress the function of the adrenal cortex for longer than 24 h, even after a single induction dose [14]. Thus, the rationale for the clinical use of etomidate has been vigorously debated. Nevertheless, no evidence of excess mortality has been associated with the use of etomidate [15]. We believe that, in spinal cord tumor resection surgery or complex spinal deformity correction surgery, patients do not have sepsis. Moreover, corticosteroids are utilized routinely, although their use is controversial [16, 17]. Thus, the use of etomidate in this kind of surgery should not cause significant adverse effects. The results of an animal study by Sloan and Roger have suggested that etomidate has dual effects on MEPs. At lower doses, etomidate will amplify the amplitudes of SSEPs, but, at relatively higher doses, the drug will depress the amplitudes of SSEPs [10]. This finding suggests that
Ir J Med Sci
etomidate could possibly be applied at a low dose to facilitate EP monitoring. Conversely, when used at a low dose, the depressive effects of etomidate on the adrenal cortex might be attenuated. Thus, we were motivated to conduct the current clinical study in order to explore whether a suitable dose of etomidate exists for IOM. We sought to establish whether etomidate could exert an amplification effect at a low dose in a propofol and remifentanil background. The results of our study demonstrated that, in a TIVA background mainly consisting of propofol and remifentanil, etomidate doses less than 0.3 mg/kg did not exhibit dual effects on SSEPs. The amplification effect on SSEP amplitudes increased following dose escalation. We might infer from this finding that the critical dose at which amplification no longer occurs is higher than 0.3 mg/kg. Another phenomenon that was observed in this study was the variability of the etomidate effects. In each treatment group, some cases exhibited no effects, whereas others showed a dose-related amplification of SSEP amplitudes. One explanation might be that, although etomidate can amplify the amplitudes of SSEP, this effect is not strong enough in some cases to overcome its depression by propofol. In clinical practice, to enhance the SSEP amplification effect, etomidate should be infused continuously, such that its total dose will be significantly higher. Considering the possible dose-related adrenal cortical depressive effects, we believe that increasing the etomidate dose to achieve better amplification of SSEPs is impractical. Thus, in order to optimize the anesthesia plan for difficult cases, other medications, such as a2 receptor agonists [18, 19] or NMDA receptor antagonists [20, 21], can be applied as auxiliary treatments. By reducing the amounts of remifentanil and propofol, the inhibition effects might be attenuated.
Conclusion Small doses of etomidate less than 0.3 mg/kg exhibited dose-related amplification effects on SSEP monitoring, but these effects exhibited considerable variability. Conflict of interest of interest.
The authors declare that they have no conflict
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