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effects on intraoperative neurophysiological monitoring JongHae Kim Department of Anesthesiology and Pain Medicine School of Medicine, Catholic University of Daegu Contents

• Effects on Sensory evoked potentials Somatosensory evoked potential Brainstem auditory evoked potential Visual evoked potential • Effects on Motor evoked potential Pharmacologic Effects of on Sensory Evoked Potentials

Somatosensory Evoked Potentials Brainstem Auditory Evoked Potentials Visual Evoked Potentials Volatile Anesthetics General Characteristics

• Synaptic transmission > axonal conduction • Polysynaptic pathway (cortical recordings) > Oligosynaptic pathway (spinal cord and subcortical recording) • VEP (cortical activity) > BAEP (brainstem and subcortical activities) General Characteristics

• ↑SSEP latency, • ↑central conduction time, • ↓amplitude • Dose dependent • Minimally affect the subcortical waveform

Effect of Inhaled Anesthetics on SSEP (Anesthesiology 2003;99:716-37) Morphologic changes of waveforms

c)

ANESTHESIOLOGY 1986;65:35–40 and

• Like isoflurane • Permit higher concentrations • At ≤1.5 MAC, ↑cortical latency, ↓amplitude, minimal effects on subcortical SSEP General Characteristics

• 60-70% of N2O: ↓ cortical SSEP amplitude 50% • Cortical latency and subcortical waves unaffected • Potentiates effect of volatile and IV anesthetics Morphologic changes of waveforms and compounding effects

of N2O c) Isoflurane

ANESTHESIOLOGY 1986;65:35–40 Compounding effects of N2O on early cortical waveform

Anesthetic Early cortical Waveform Drug/Concentration Latency Amplitude

1.5 MAC + 60% N2O 10-15% ↑ ~80% ↓ 1.5 MAC (alone) 10-15% ↑ ~70% ↓

1.5 MAC + 60% N2O Not recordable Not recordable 1.5 MAC (alone) > 25% ↑ ~85% ↓ Desflurane

1.5 MAC + 65% N2O Complete loss of waveform Complete loss of waveform 1.5 MAC ≤ 10% ↑ < 50% ↓ Compounding effects of N2O on early cortical waveform

Anesthetic Early cortical Waveform Subcortical Waveform Drug/Concentration Latency Amplitude Isoflurane

0.5 MAC + 60% N2O < 10% ↑ 50-70% ↓ Negligible 0.5 MAC (alone) < 15% ↑ < 30% ↑ Negligible

1.0 MAC + 60% N2O 10-15% ↑ 50-75% ↓ Negligible 1.0 MAC (alone) 15% ↑ ≒50% ↓ Negligible

1.5 MAC + 60% N2O > 15% ↑ > 75% ↓ 5% ↑ in latency 1.6 MAC (alone) 15-20% ↑ 60-70% ↓ 5% ↑ in latency 20% ↓ in amplitude Intravenous Anesthetics General Characteristics

• Affect SSEP less than inhaled anesthetics • Low doses: minimal effects • High doses: slight-moderate ↓amplitude and ↑latency • Subcortical potentials unaffected

• Dose-dependent ↑in latency, ↓in amplitude in early cortical SSEP • Cortical waves are affected more than subcortical, midlatency waveforms • Synaptic transmission > axonal conduction (≒ volatile anesthetics) • Thiopental (5 mg/kg): latency 10-20% ↑, amplitude 20-30% ↓ (less than 10 min) • coma allows recording cortical SSEPs

Barbiturates

Drug/Dose Early Cortical Subcortical Waveform Waveform Latency Amplitude Thiopental 2.5-5.0 mg/kg <10% ↑ 5-30% ↓ Negligible 75 mg/kg 15% ↑ 60% ↓ Negligible Up to 20 mg/kg ≒ 10% ↑ 45% ↓ None (latency) 20% ↓(amplitude) Etomidate

• Increases cortical SSEP amplitude (400%) Not related to myoclonus1 d/t altered balance btw inhibitory and excitatory influences at the cerebral cortex level2 • Decreases subcortical amplitude (50%)

1. Kochs E, Treede RD, Schulte J: Increase in somatosensory evoked potentials during anesthesia induction with etomidate. Anaesthesist 1986; 35:359–64 2. Samra SK, Sorkin LS: Enhancement of somatosensory evoked potentials by etomidate in cats: An investigation of its site of action. ANESTHESIOLOGY 1991; 74:499–503

• Increases cortical SSEP amplitude (max. effect within 2-10 min of bolus) ≒etomidate • No effect on cortical latency or subcortical waveforms

Etomidate and Ketamine

Drug/Dose Early Cortical Waveform Subcortical Latency Amplitude Waveform Etomidate 0.3-0.4 mg/kg + 2 mg/kg/h <10% ↑ 40-180% ↑ None (latency) 50% ↓(amplitude) 1 mg/kg 10% ↑ 150% ↓ Negligible Ketamine 0.5 mg/kg No effect No effect No effect 2-3 mg/kg + 2 mg/kg/h No effect 0-30% ↑ Negligible

• ≒ Barbiturates • Rapid emergence for timely postop. neurologic assessment • 2.5 mg/kg: no changes in cortical and subcortical amplitudes, increased cortical latency (8%) and CCT (20%)

• Cortical SSEP is best preserved (> N2O, , sevoflurane) Propofol

Drug/Dose Early Cortical Waveform Subcortical Latency Amplitude Waveform 2.5 mg/kg <10% ↑ No change Negligible 2.5 mg/kg, then 10 mg/kg/h 10-15% ↑ 50% NA + 0.5 mcg, then 0.25 mcg/kg/h

• (0.1-0.25 mg/kg): mild↓ in N- 20 amplitude, moderate ↓ in later wave cortical amplitude, abolished very long latency peaks (200-400 ms) • Midazolam (0.2-0.3 mg/kg): modest ↓ in amplitude, slight ↑of latency Benzodiazepine

Drug/Dose Early Cortical Waveform Subcortical Latency Amplitude Waveform Midazolam 0.1-0.3 mg/kg <5% ↑ 25-40% ↓ Negligible Diazepam 0.1-0.25 mg/kg Minimal ↓ NA

• Unimportant changes in latency and amplitude • No significant effect on SSEP (up to 130 mcg/kg), Bolus > Infusion • : modest amplitude depression • < fentanyl

Opioids

• Subarachnoid meperidine blocks voltage- dependent Na+ channels: 60%↓amplitude, 10%↑latency • Subarachoid fentanyl (25 mcg), (20 mcg/kg) + sufentanil (50 mcg), morphine (15 mcg/kg): no significant chagnes Opioids

Drug/Dose Early Cortical Waveform Subcortical Latency Amplitude Waveform Morphine 0.25 mg/kg < 10% ↑ ≒ 20% ↓ NA Fentanyl

2.5 mcg/kg + N2O 5-10% ↑ Variable No change 25-100 mcg/kg < 10% ↑ 10-30% ↓ Negligible Sufentanil

Sufentanil + N2O + 5-10% ↑ ≒ 50% ↓ No change 0.5%isoflurane/1 mcg/kg + infusion 5 mcg/kg Sufentanil (alone) ≒ 5% ↑ ≒ 40% ↓ No change (latency) Amplitude: 40% ↓ 1 mcg/kg + Sufentanil 5-10% ↑ No change NA propofol Opioids

Drug/Dose Early Cortical Waveform Subcortical Latency Amplitude Waveform Remifentanil (with 0.4 MAC isoflurane) 1 mcg/kg + 0.2 NA 15-30% ↓ NA mcg/kg/min 2.5 mcg/kg + 0.5 30-40% ↓ mcg/kg/min 5.0 mcg/kg + 1.0 ≒ 40% ↓ mcg/kg/min Alfenanil 10 mcg/kg alone NA 50% ↓ NA

100 mcg/kg + 2 with N2O No effect 40% ↓ Clonidine and

• Clonidine: no change in latency and amplitude • Dexmedetomidine: affects amplitude minimally • During isoflurane anesthesia, dexmedetomidine blunts isoflurane’s effect on SSEP amplitude1.

1. Bloom M, Beric A, Bekker A: Dexmedetomidine infusion and somatosensory evoked potentials. J Neurosurg Anesthesiol 2001; 13:320–2 Clonidine and Dexmedetomidine

Drug/Dose Early Cortical Waveform Subcortical Latency Amplitude Waveform Clonidine 2-10 mcg/kg No effect No effect 10% Amplitude ↓ No effect (latency) Dexmedetomidine Low dose NA ≒ 10% ↓ ≒ 20% Amplitude ↓ High sedative dose NA ≒ 30% ↓ ≒ 10% Amplitude ↓ Neuromuscular Blocking Drugs

• No effects on SSEP, BAEP, or VEP • Improve waveform quality through elimination of the EMG artifact Regional Administration

• Local infiltration & subarachnoid block: abolish SSEPs • Epidural block: depends on dose and dermatome • IV lidocaine: unlikely to interfere with intraop. monitoring

Drug/Dose Early Cortical Waveform Subcortical Latency Amplitude Waveform Lidocaine 1.5 mg/kg, then 3 mg/kg/h 5% ↑ 25-30% ↓ Negligible Implications for Perioperative Monitoring • Volatile anesthetics: 1.0 MAC alone • Desflurane or sevoflurane: 1.5-1.75 MAC • IV anesthetics > volatile anesthetics • Propofol-sufentanil reduce amplitude significantly1

1. Borrissov B, Langeron O, Lille F, Gomola A, Saillant G, Riou B, Viars P: Combination of propofol-sufentanil on somatosensory evoked potentials in surgery of the spine. Ann Francaises d Anesth et de Reanimation 1995; 14:326–30 Implications for Perioperative Monitoring • Preserve amplitude ! • Low baseline amplitude: > 50 yr, congenital scoliosis, paralytic scoliosis, spinal stenosis, spinal tumor, other preexisting neurologic deficits

Strategies to Enhance the amplitude and reproducibility of SSEPs • High-pass 30-Hz digital filtering1

• Substitution of propofol for N2O • Eliminating N2O • Substitution of remifentanil for fentanyl & N2O • If N2O is necessary, combine it with midazolam2 • Adjuncts(dexmedetomidine, clonidine, neuroaxial opioids) reduce MAC

1. Kalkman CJ, ten Brink SA, Been HD, Bovill JG: Variability of somatosensory cortical evoked potentials during spinal surgery: Effects of anesthetic techniques and high-pass digital filtering. Spine 1991; 16:924–9 2. Koht A, Schutz W, Schmidt G, Schramm J, Watanabe E: Effects of etomidate, midazolam, and thiopental on median nerve somatosensory evoked potentials and the additive effects of fentanyl and nitrous oxide. Anesth Analg 1988;67:435–41 Strategies to Enhance the amplitude and reproducibility of SSEPs • Ketamine • Etomidate: bolus 0.5-1 mg/kg + infusion 20-30 mcg/kg/min1 • Low concentrations of volatile anesthetics + etomidate or propofol (anesthetic depth) + vasodilator and β- blocker (control BP and myocaridal stress) • Sevoflurane permits faster SSEP recovery2

1. Sloan TB, Ronai AK, Toleikis JR, Koht A: Improvement of intraoperativesomatosensory evoked potentials by etomidate. Anesth Analg 1988; 67:582–5 2. Ku ASW, Irwin MG, Chow B, Gunawardene S, Tan EE, Luk KDK: 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; 88:502–7 Summary (Periop. Implications)

• Volatile anesthetics: 0.5 MAC with N2O or 1.0 MAC without N2O • Desflurane, Sevoflurane: higher conc. • IV anesthetics and (propofol, midazolam, remifentanil) • Avoid sudden anesthetic depth change during surgical manipulation • Latency stabilization: 5-8 min after conc. change • Otherwise, etomidate or ketamine Pharmacologic Effects of Anesthetics on Sensory Evoked Potentials

Somatosensory Evoked Potentials Brainstem Auditory Evoked Potentials Visual Evoked Potentials Schematic of Auditory Neural Pathway

Black S, Mahla ME, Cucchiara RE: Neurologic Monitoring, 5th edition. Edited by Miller RD. Philadelphia, Churchill Livingston, 2000, p 1339 Anesthetic Effect on Brainstem Auditory Evoked Potentials Inhaled Anesthetics

• Increases in latency • No effect on amplitude

• N2O: no effect on latency and amplitude, increasing middle ear pressure prolongs latency in hearing impairment pts. Inhaled Anesthetics

Anesthetic Drug Dose/Concentration Latency Wave V Amplitude Wave V Volatile agents Up to 1.5 MAC < 10% ↑ No effect Nitrous oxide 50% No effect Inconsistent Influence of isoflurane alone on brainstem auditory evoked potential in a typical subject

Manninen PH, Lam AM, Nicholas JF: The effects of isoflurane-nitrous oxide anesthesia on brainstem auditory evoked potentials in humans. Anesth Analg 1985; 64:43–7.) Intravenous Anesthetics Thiopental

• No effect • 77.5 mg/kg: latency 10%↑ • Recordable in isoelectric EEG1

1. Drummond JC, Todd MM, U HS: The effect of high dose on brainstem auditory and median somatosensory evoked responses in humans. ANESTHESIOLOGY 1985; 63:249–54 Propofol

• 2 mg/kg followed by a continuous infusion: latency ↑(<5%) • No effect on amplitude Thiopental and Propofol

Anesthetic Drug Dose/Concentration Latency Wave V Amplitude Wave V Thiopental 4-6 mg/kg No effect No effect 75 mg/kg ≒ 10% ↑ < 20% ↓ Propofol 10-50 mcg/kg/min No effect No effect No effect

• Etomidate (10-50 ㎍/kg/min) • Ketamine (2 mg/kg) • Fentanyl • Alfentanil • Sufentanil • Morphine • Benzodiazepine Other intravenous anesthetics

Anesthetic Drug Dose/Concentration Latency Wave V Amplitude Wave V Etomidate 4-6 mg/kg No effect No effect Midazolam 0.2-0.3 mg/kg No effect NA Diazepam 0.3-0.4 mg/kg No effect NA Fentanyl 10-50 mcg/kg No effect No effect Sufentanil 5 mcg/kg No effect NA Alfentanil 100-500 mcg/kg No effect No effect Morphine 1-3 mg/kg No effect No effect Lidocaine 60 mcg/kg/min < 5% ↑ No effect Ketamine 2 mg/kg No effect No effect Clonidine 10 mcg/kg No effect No effect Implications for Perioperative Monitoring • BAEP waves I-V: no limitations on anesthetic technique Pharmacologic Effects of Anesthetics on Sensory Evoked Potentials

Somatosensory Evoked Potentials Brainstem Auditory Evoked Potentials Visual Evoked Potentials

Inhaled Anesthetics

• Prolong latency and decrease amplitude in a dose dependent manner • 1.5 MAC: non-interpretable

• N2O: severely attenuates amplitude • Its addition to volatile anesthetics: unrecordable Inhaled Anesthetics

Anesthetic Drug Dose/Concentration Latency of P-100 Amplitude Halothane 1 MAC ≒ 10% ↑ Inconsistent Isoflurane 0.5 MAC 10% ↑ 40% ↓ 1.0 MAC 20% ↑ 66% ↓ 1.5 MAC 30% ↑ 80% ↓

1.0 MAC + 70% N2O Abolished Abolished

1.5 MAC + 70% N2O Abolished Abolished

Sevoflurane 0.5 MAC + 66% N2O 5-10% ↑ 20% ↓

1 MAC + 66% N2O Abolished Abolished

1.5 MAC + 66% N2O Abolished Abolished 1.4-1.7 MAC Abolished Abolished Nitrous Oxide 10-50% No effect 25-80% ↓ Chi OZ, Field C: Effects of isoflurane on visual evoked potentials in humans. ANESTHESIOLOGY 1986; 65:328–30 Intravenous Agents

• Thiopental: ↓amplitude, ↑latency • Etomidate: ↑latency, no change in amplitude • Fentanyl (10-60 ㎍/kg): 30% amplitude ↓ Intravenous Agents

Anesthetic Drug Dose/Concentration Latency of P- Amplitude 100 Propofol 2 mg/kg + 10 mg/kg/h Negligible ≒ 20% ↓ Thiopental 3 mg/kg < 10% ↑ No change 6 mg/kg Abolished Abolished Etomidate 0.3 mg/kg < 10% ↑ No change Fentanyl 10-60 mcg/kg < 10% ↑ 30% ↓ Ketamine 1 mg/kg + 2 mg/kg/h Negligible ≒ 60% ↓ Implications for Intraoperative Monitoring • Polysynaptic cortical activity: very sensitive to anesthetics • Opioid, propofol, ketamine, low dose

volatile anesthetics without N2O • Abandoned for intraop. application (a high incidence of false positive and false negative)

Pharmacologic Effects of Anesthetics on Motor Evoked Potentials de Haan P, Kalkman CJ, Jacobs MJ: Thorac. Cordiovasc. Surg. 1998;10:19–24 Volatile Anesthetics

• Dose-dependent depression of amplitudes • Inhibit the pyramidal activation of spinal motor neurons at the ventral horn level • Single pulse transcranial stimuli cannot overcome the suppressive effect of 0.25- 0.5 MAC

Volatile Anesthetics

• Suppression overcome by higher- intensity stimuli, multi pulse stimulation and direct stimulation of motor cortex • Much less effect on spinal D-wave Volatile Anesthetics

Agent Type of Stimulus Mean Amplitude(%) Patients with Stimulus Paradigm Amplitude of Baseline Responses (mcV) (%) Isoflurane TcE 3 pulse 441 61 100 0.16 MAC 5 pulse 560 74 100 Isoflurane TcE 3 pulse 293 40 100 0.3 MAC 5 pulse 337 44 100 Isoflurane TcE 3 pulse 172 24 90 0.5 MAC 5 pulse 184 24 90 Isoflurane TcE 4 pulse 92 61 0.75 to 1 MAC 5 pulse 8 Volatile Anesthetics

Agent Type of Stimulus Mean Amplitude(%) Patients with Stimulus Paradigm Amplitude of Baseline Responses (%) (mcV) Sevoflurane TcE 2 pulse 37 27 85 0.25 MAC Sevoflurane TcE 2 pulse 10 7 55 0.5 MAC Sevoflurane TcE 2 pulse 0 0 10 0.75 MAC Sevoflurane TcE 2 pulse 0 0 0 1.0 MAC Ubags LH, Kalkman CJ, Been HD: Neurosurgery 1998;43:90–94 Nitrous Oxide

• Less suppressive than inhaled agents • Multi-pulse stimulation reverses amplitude depression • Little effect on the D-wave (recordable at

70% N2O) Nitrous Oxide

Agent Type of Stimulus Mean Amplitude(%) Patients with Stimulus Paradigm Amplitude of Baseline Responses (%) (mcV)

50% N2O TcE 1 pulse 401 27 100 TcE 2 pulse 1,031/629/ 100/100 430 TcM 1 pulse 192 55 55

60% N2O TcE 6 pulse 450 100 Barbiturates

• Dose dependent decrease in amplitudes • Thiopental (4-9 mg/kg): complete loss • (≒ etomidate) is better than thiopental and propofol Propofol

• Despite depressive effect, it provides early postop. emergence for neurologic exam • Suppresses α motor neuron at spinal gray matter level • Multi-pulse stimulation improves response amplitude Propofol

• ≤ 1㎍/ml: intact CMAP response • 1-2 ㎍/ml: 30-60 % reduction in amplitude • ≥ 3 ㎍/ml: great variability in response depression

van Dongen EP, ter Beek HT, Aarts LP, et al. The effect of two low-dose propofol infusions on the relationship between six-pulse transcranial electrical stimulation and the evoked lower extremity muscle response. Acta Anaesthesiol Scand. 2000;44:799–803. Propofol

Dose Type of Stimulus Mean Amplitude(%) Patients with (mcg/kg/min) Stimulus Paradigm Amplitude of Baseline Responses (%) (mcV) 20-25 TcE 2 pulse 638 85 100 TcE 6 pulse 813 100 TcM 5 pulse 2503 86 25-50 TcE 2 pulse 519 69 100 TcE 6 pulse 526/28 28 TcM 5 pulse 822 28 92-100 50-75 TcE 5 pulse 23 23 80 75-100 TcE 2 pulse 655 63 83 TcE 5 pulse 13/305/125 13 60/88 TcM 5 pulse 560 19 > 100 TcE 4 pulse 134 96 TcM 5 pulse 355 12 Etomidate

• Minimal suppression • 0.3 mg/kg: amplitude depression to 35% of baseline, no latency changes for 2-5 minutes • 10-30 ㎍/kg/min: success in obtaining potentials • Disinhibition of extrapyramidal system, brain stem, spinal cord excites motor system Ketamine

• Minimal effects (low-dose bolus ≤ 0.5 mg/kg or infusion 1-4 mg/kg/h) • S/E: emergence delirium, hallucinations, nightmare (reduced by adding propofol 15-50 ㎍/kg/min to ketamine infusion)

Opioids

• Minimal effects (low-dose infusion) • Equal suppression following fentanyl (longer effects), sufentanil, alfentanil • Dose-dependent CMAP depression (50% of baseline) at dose for surgical anesthesia • Remifentanil is less suppressive

• Less depressive than propofol or thiopental • Diazepam for premedication: little effect • Midazolam Single-pulse: decrease CMAP response Multi-pulse: no significant effects Etomidate, Ketamine, Opioids, and Benzodiazepines

Agent Type of Stimulus Mean Amplitude(%) Patients with Stimulus Paradigm Amplitude of Baseline Responses (%) (mcV) Etomidate 5-10 TcM 1 pulse 229 93 77 mcg/kg/min TcE 1 pulse 1062 100 Ketamine TcE 3 pulse 60 91 1 mg/kg/hr 5 pulse 400 100 Etomidate, Ketamine, Opioids, and Benzodiazepines Agent Type of Stimulus Mean Amplitude(%) Patients with Stimulus Paradigm Amplitude of Baseline Responses (%) (mcV) Sufentanil TcE 1 pulse 401 86 100 0.5 mcg/kg/hr TcE 2 pulse 311/1031 69 100 TcE 3 pulse 287 28 100 Remifentanil TcM 2 pulse 750 40 9 ng/ml 4 pulse 1500 50 Midazolam TcM 1 pulse 525 198 87 0.1 mg/kg/hr Neuromuscular Blockade

• Maintain balance between surgical relaxation and CMAP responses • Maintaining T1 20-50% using a single twitch M-response facilitates surgery and allows reproducible response • T1 44-55% with 6-pulse stimulus produce amplitudes in nonparalyzed conditions

Neuromuscular Blockade

Neuromuscluar Type of Stimulus Mean Amplitude(%) Patients with blockade T1 Stimulus Paradigm Amplitude of Baseline Responses (%) (mcV) 45-55% baseline TcE 2 pulse 105 180 100 TcE 6 pulse 948 97 100 15-20% baseline TcE 1 pulse 600 56 95 5-15% baseline TcE 6 pulse 272 28 100 Implications for Perioperative Monitoring • Neurogenic MEP: resistant to anesthetic depression • IV agents: less depression • A combination of propofol and remifentanil: excellent experience

Implications for Perioperative Monitoring • MEP at spinal level: less serious • MEP at muscle: maintain T1 at 30% of baseline, otherwise profound relaxation

• TIVA better than N2O or inhaled agents

Adding 0.3 MAC isoflurane to TIVA using propofol and remifentanil Summary (SEP)

• Inhalational agents produce dose-related decreases in amplitude and increases in latency (cortical > subcortical, spinal and peripheral evoked responses) • Opioids produce less marked changes • Ketamine and etomidate increase amplitude of cortically generated SSEP Summary (SEP)

• IV sedative- drugs (droperidol, barbiturates, benzodiazepines, etomidate, propofol) produce dose-related depression to a less extent than the inhalation agents do • Muscle relaxants have minimal effect Summary (MEP)

• TIVA (opioids, ketamine, etomidate, and midazolam) provide success for intraop. monitoring • Higher pulse stimulus paradigms under low concentrations of propofol or volatile anesthetics improve monitoring • A continuous infusion is preferable to a bolus

Conclusions

• Tailored anesthetics to optimize the recorded responses • Preoperative planning and cooperation between the surgeon, anesthesiologist, and neurophysiologist are imperative Thank you for your attention!~