- Intraoperative neuromonitoring can be exquisitely sensitive to the effects of various anesthetic and analgesic agents.
- The impact of opioid-sparing multimodal analgesic strategies on intraoperative neuromonitoring remains poorly characterized.
- The effects of any pharmacological agents on intraoperative neuromonitoring can be considerably dependent on dosing regimens, patient characteristics, and pre-existing comorbidities.
- The paucity of high-quality clinical evidence on the effects of multimodal analgesic agents on intraoperative neuromonitoring makes it challenging to make a definitive recommendation for or against a specific multimodal analgesic intervention or regimen in the setting where neuromonitoring is required.
Intraoperative neuromonitoring (IONM) is commonly used during surgeries in which neural pathways are at risk to provide real-time information about the functional integrity of these pathways and to monitor for injury. Such monitoring allows interventions (both surgical and anesthetic) that can potentially prevent permanent iatrogenic neurological injury. It is well-recognized that many anesthetic agents degrade intraoperative evoked potential signals, particularly in pathways that involve multiple synapses, and that this can compromise the quality of monitoring.1 As such, transcranial motor evoked potentials (TcMEPs) and somatosensory evoked potentials (SSEPs), which are among the most commonly used neuromonitoring modalities, are at particular risk for signal degradation. With increasing interest in the use of multimodal analgesia, in addition to considering anesthetic needs that are unique to the surgical procedure and patient-specific comorbidities,2 anesthesiologists must also understand the potential impact of adjunctive anesthetic and analgesic agents on neuromonitoring to facilitate the high-fidelity signal acquisition. The focused review aims to delineate the potential impact of certain commonly used adjunctive anesthetic and analgesic agents on routine intraoperative evoked potential modalities.
Multimodal analgesic strategies have gained traction in recent years as practitioners have become more cognizant of the short-term and long-term sequalae of opioid-based regimens for perioperative pain management.3 This is particularly relevant among patients undergoing spine procedures, which have been frequently associated with significant postoperative pain. In the sections which follow, we discuss the effects of multimodal neuromonitoring of many of the common analgesic adjuncts that are employed in the clinical setting (Table 1).
TABLE 1 -
Multimodal Analgesic Drug Effects on Intraoperative Neuromonitoring
||→ / ↓
||→ / ↓
||→ / ↓
||↑ / ↓ (large bolus)
↑, increase; ↓, decrease; →, no change.
N/A indicates not available; SSEP, somatosensory evoked potential; TcMEP, transcranial motor evoked potential.
Ketamine, a potent N-methyl-D-aspartate (NMDA) receptor antagonist, has been an important component of multimodal analgesic strategies in the perioperative setting.4 Its analgesic property, while remaining poorly understood, appears to be mediated through both supraspinal and peripheral pathways.4 While ketamine is traditionally known for its augmentative effect on IONM signals (thought to be the result of a complex interaction with glutamate, norepinephrine, and 5-hydroxytryptamine centrally), there has been a lack of robust clinical data from prospective randomized studies to support this notion.5,6 Indeed, earlier randomized studies have yielded conflicting results regarding the augmentative effect of ketamine on TcMEPs.7,8 In a recent retrospective cohort of 35 patients undergoing spine surgery, Lam et al9 reported no statistically significant difference in TcMEP amplitude and latency from baseline between those who received ketamine infusions and those who received dexmedetomidine infusions in addition to propofol for anesthetic maintenance.9 In a double-blinded randomized controlled trial (RCT) involving 20 adolescents undergoing scoliosis surgery randomized to receive either ketamine 1 mg/kg bolus or normal saline, TcMEPs were measured at baseline and up to 10 minutes following the randomized interventions.10 Interestingly, the authors reported a statistically and clinically significant reduction in TcMEP amplitude across all muscles as compared with baseline for up to 10 minutes following ketamine bolus, though the SSEP latency and amplitude remained unchanged from baseline. While it remains unclear at the present time whether ketamine has a neutral or an augmentative effect on IONM signals, it is evident that a depressive effect may occur when ketamine is administered as a higher-dose bolus. In the clinical setting, ketamine can be safely administered as a 0.25 to 0.5 mg/kg bolus followed by a 0.25 to 0.5 mg/kg/h infusion, and the concomitant reduction in hypnotic requirement will aid to reduce the deleterious effect of other general anesthetic agents on IONM quality.
Dexmedetomidine, a central and peripheral α2 adrenergic receptor agonist, is an effective opioid-sparing analgesic modality for neurosurgical patients.11 Earlier literature has reported conflicting results regarding the compatibility of dexmedetomidine with IONM, though such pharmacological interaction appeared to be, to a certain extent, dose-dependent.12–19 Theoretically, dexmedetomidine could inhibit evoked potentials by increasing inhibitory synaptic transmission through activation of the descending noradrenergic system.20 In a retrospective, observational study of 78 patients undergoing intracranial tumor resections, patients who received dexmedetomidine 0.5 mcg/kg bolus followed by 0.5 mcg/kg/h infusion had significantly higher TcMEP stimulation thresholds as compared with a control group, while SSEP stimulation thresholds were not significantly different between the 2 groups;21 TcMEP amplitudes in both upper and lower extremities were also significantly lower among those who received dexmedetomidine. In a retrospective case-controlled study of 70 pediatric patients undergoing posterior spine surgery, dexmedetomidine infusion at 0.3 to 0.5 mcg/kg/h without bolus was associated with a statistically and clinically significant reduction in TcMEP amplitude from baseline.22 In a prospective, double-blinded RCT by Pacreu et al,23 40 patients undergoing intracranial tumor resections were randomized to receive either dexmedetomidine 0.5 mcg/kg/h infusion without bolus or normal saline infusion, in addition to propofol and remifentanil infusions for anesthesia maintenance;23 TcMEP stimulation threshold was significantly higher in the dexmedetomidine group, though the TcMEP and SSEP amplitudes were not different between the 2 groups. In a double-blinded RCT involving 160 patients undergoing thoracic spine surgery, participants were randomized to receive either dexmedetomidine 1 mcg/kg bolus followed by 0.5 mcg/kg/h infusion, dexmedetomidine 0.5 mcg/kg/h infusion without bolus, or placebo infusion.20 The authors reported, through within-group analysis, a significant decrease in TcMEP and SSEP amplitudes and a significant increase in SSEP latencies for up to 25 minutes following the administration of dexmedetomidine bolus and infusion; this phenomenon was not observed in the placebo group or in the dexmedetomidine infusion only group. Taken together, dexmedetomidine, while apparently compatible with IONM at low-doses, may elicit a dose-dependent suppression of SSEP and TcMEP amplitudes at higher doses. Clinicians should be mindful that, with a 3-compartment pharmacokinetic model of dexmedetomidine, the plasma concentration gradually increases over the intraoperative course even when the infusion dose is held constant; thus, the adverse effect of dexmedetomidine on IONM may become exaggerated with longer procedures.24 Based on the present literature, it appears that dexmedetomidine can be administered as a low-dose infusion of 0.3 to 0.5 mcg/kg/h in the setting of IONM, with the understanding that the infusion should likely be adjusted to a lower infusion rate over the course of a long surgery to reduce the potentially deleterious effect of “anesthetic fade” on signal quality.
Lidocaine infusion has demonstrated efficacy as a co-analgesic in various surgical populations that include both intracranial and spine surgery patients.25,26 While its exact mechanism of action remains elusive, it has been postulated that lidocaine exerts its antinociceptive, anti-inflammatory, and anti-hyperanalgesic properties through both central and peripheral pathways.27 Earlier studies reported conflicting effects of lidocaine infusions on IONM when used in clinically relevant doses, and a possible depression of signals has been postulated to be the result of partial inactivation of sodium channels.28–31 In an open-label, assessor-blinded, randomized cross-over study involving 40 patients undergoing multilevel spine surgery, subjects were randomized to first receive either propofol 50 mcg/kg/min infusion or lidocaine 1 mg/kg bolus followed by 1 mg/kg/h infusion in addition to a propofol 25 mcg/kg/min infusion in a cross-over fashion.32 In addition, anesthesia in all subjects was maintained with a balanced combination of isoflurane, fentanyl infusion, and ketamine infusion. The authors reported no statistically significant difference in TcMEP threshold voltages or in SSEP amplitudes by within-patient analysis. In an open-label, assessor-blinded RCT, 40 patients undergoing craniotomy for tumor resection were randomized to receive either lidocaine 1 mg/kg bolus followed by 1 mg/kg/h infusion or normal saline.33 In addition, all patients received propofol, remifentanil, and cisatracurium infusions for the maintenance of anesthesia. The authors reported no statistically significant difference in TcMEP amplitudes or latencies at 35 min and 50 min post-induction of anesthesia between the 2 treatment groups. Based on the limited evidence to date, it appears that lidocaine administered as a 1 mg/kg bolus followed by a 1 to 1.5 mg/kg/h infusion does not significantly impact the quality of IONM signals.
Magnesium, an NMDA receptor antagonist, has been proposed as a nonopioid analgesic alternative for patients undergoing spine procedures.2 While the well-known inhibitory effect of magnesium on presynaptic acetylcholine release at the neuromuscular junction raises the question of whether magnesium could potentially be deleterious to IONM, such a concern has not been validated in a prospective manner, and such a phenomenon has not been reported apart from in a single case report in 2018.34 With its known effect on the neuromuscular blockade, it does not seem advisable to incorporate magnesium as a routine analgesic modality during TcMEP monitoring until more evidence is available. An ongoing prospective, double-blinded RCT evaluating the effect of magnesium as a 40 mg/kg bolus followed by a 10 mg/kg/h infusion versus placebo on SSEPs and TcMEPs may offer insight into this question (NCT04938765).
Gabapentinoids, through their interaction with the α2δ subunit of the voltage-gated calcium channel, has gained some popularity in recent years as opioid-sparing adjuncts in the perioperative setting, though this popularity has declined significantly in recent years owing to the emerging evidence for the neurocognitive side-effects of these agents.35 The effect of gabapentinoids on IONM, however, has not been reported in the literature. The non-linear pharmacokinetics and the unpredictable oral bioavailability of gabapentinoids make it difficult to examine their interactions with IONM in the clinical setting.36 Without evidence to suggest the contrary, and with common clinical practice supporting its nonharmful effects on neuromonitoring signals, the perioperative administration of gabapentinoids appear to be acceptable in this regard.
Methadone, which is both an µ-opioid agonist and an NMDA receptor antagonist, has gained traction in recent years as an analgesic adjunct in patients having spine surgery.37 The effect of methadone on IONM, however, has not been well-characterized in the literature. In a prospective, nonrandomized, noncomparative study of 17 adult patients undergoing spine surgery, SSEPs and TcMEPs were measured at 0-, 5-, 10- and 15-minutes following the administration of a 0.2 mg/kg intravenous bolus of methadone;38 general anesthesia was maintained with a propofol infusion only to avoid the potential confounding effects of other pharmacological agents. While the authors reported a statistically significant increase in SSEP latencies and a decrease in SSEP amplitudes following methadone administration, the reported changes fell below what would otherwise be considered the clinically significant alert criteria. Of note, no statistically significant effects on TcMEP latency and amplitude were observed. Given the limitation of a small nonrandomized study with multiple confounders, and the fact that IONM was measured only for 15 minutes following methadone administration in this study, conclusions cannot be drawn with regard to the compatibility of methadone with IONM in this setting. However, clinical experience suggests that a 0.2 mg/kg bolus of intravenous methadone at the time of induction appears to be compatible with IONM.37
FUTURE RESEARCH AND CHALLENGES
There is currently a paucity of clinical evidence from high-quality, prospective, randomized studies on the effects of multimodal analgesics on IONM. The few prospective randomized studies that do exist are mostly single-centered with small sample sizes. There is also significant variability in study designs, measured outcomes, dosing regimens (including background anesthetic agents), and patient populations, making it difficult to compare the results of 1 study with another. Indeed, the impact of excessive depth of anesthesia may amplify the otherwise trivial effects of analgesic agents on IONM quality; as the objective (ie, numerical) measurement of anesthetic depth is seldomly reported in the neuromonitoring literature, this serves as yet another potential confounding variable. This is further complicated by the fact that no universally-accepted alarm criteria for IONM modalities currently exist, and even the long-established alert criteria for SSEPs have been recently questioned with a call to change to an “adaptive warning criterion”.39 Furthermore, the complex interplay of physiological, pharmacological, pathologic, surgical, and technical factors that may influence IONM quality makes it a challenging undertaking to design a prospective study on this topic that can be externally validated. With these challenges, more robust information may not be immediately forthcoming.
Striking a balance between achieving adequate multimodal analgesia and IONM compatibility can be challenging, as pharmacological agents administered at an effective analgesic dose may, in fact, preclude adequate signal quality. However, many of the nonopioid analgesics considered in this review could potentially reduce cortical arousal through their antinociceptive properties, and could, in turn, provide a beneficial effect for IONM signal acquisition by lowering the pharmacological requirement for hypnotic agents.2,40 Accordingly, while the current evidence does not allow a definitive recommendation for or against a specific multimodal analgesic intervention in the setting of IONM, it is evident that the effects of any pharmacological agent on IONM would be considerably dependent on dosing regimens, and that these effects are likely exaggerated in patients with pre-existing comorbidities. Thus, clinicians should understand the limitation of the available evidence to date, interpret this evidence with caution, and make clinical decisions on an individualized basis as it pertains to the integration of multimodal analgesics in settings where IONM is required.
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