In the present study, we found that short tetanic stimulation during PTC monitoring caused hemodynamic alterations in about 10% of patients under general anesthesia. These hemodynamic changes were confirmed by EEG band power changes, which were characterized by significant decreases in normalized alpha power but not in beta and delta band powers after short tetanic stimulation. Furthermore, we found that the low effect-site concentration of remifentanil and body weight were significantly associated with nociceptive responses to short tetanic stimulation during PTC monitoring.

Electrical stimulation of the ulnar nerve is considered a standard measure for predicting patients’ responses to nociceptive stimuli.8 Previous studies have detailed the effects of 100 Hz tetanic stimulation on various parameters such as pupil response, entropy, Bispectral Index™ (BIS™; Medtronic, Minneapolis, MN, USA), skin conductance, and hemodynamics.11,30,31,32,33,34 Short tetanic stimulation has also been shown to impact hemodynamics, entropy, respiratory rate intervals, and pulse plethysmography variation.9,30,35 Other studies have explored the influence of neuromuscular block and short tetanic stimulation on the BIS, auditory evoked potentials,32 and EEG power responses only in the high-frequency band.36 Unlike these studies, we report that short tetanic stimulation during PTC monitoring was associated with nociceptive responses, as shown by the characteristic loss of EEG alpha power.

Conventional nociception assessment, based on autonomic responses, such as hypertension or tachycardia,12 lacks specificity, as non-nociceptive stimulations or cardiovascular medications can also trigger these sympathetic responses.14 A more precise approach to nociception assessment uses EEG to quantify central nervous system activity, with changes in EEG band power serving as a surrogate marker for nociception discrimination.13,14 In the present study, the reduction in EEG alpha power observed in responders following short tetanic stimulation aligns with earlier research that observed alpha dropout in response to noxious stimulation.14,37 These aspects reflect an incomplete modulation of nociception after short tetanic stimulation. Nevertheless, unlike previous studies which found an increase in delta or beta power after noxious stimuli, including skin incision, surgical stimulation, tetanic stimulation (100 Hz), and laparotomy,36,38,39,40 we did not observe changes in other EEG bands. This may be due to the relatively low intensity of short tetanic stimulation (50 Hz), the moderate depth of anesthesia provided,39,41 or the use of balanced anesthesia in this study.42,43 Large-scale prospective studies are warranted to confirm this result.

Processed EEG indices could not detect the nociceptive features evident in our raw EEG power analysis. Indices such as the BIS and PSi, designed primarily for hypnosis monitoring by analyzing relatively high-frequency EEG power, have limited sensitivity to changes in lower-frequency EEG power caused by noxious stimuli.14 This limitation may stem from the proprietary algorithm of the processed EEG indices, which heavily compresses a large amount of information, resulting in the loss of specific neurophysiologic signatures.44,45 In addition, computational delays of 14–155 sec could hinder these indices’ capacity to reflect the effects of noxious stimulation promptly.

Our spectral analysis revealed that short tetanic stimulation produced distinct EEG responses, notably alpha-band reductions and broader cortical activation patterns, even without autonomic changes in some cases. A previous case report documented a similar phenomenon,46 suggesting that EEG changes can precede or occur independently of sympathetic activation. A recent study also identified alpha-band attenuation as an early, reliable marker of intraoperative pain,47 supporting its potential as a real-time analgesia monitor. Our post hoc analysis (AUROC, 0.68; sensitivity, 98%; specificity, 33%) suggests that alpha-band suppression may be highly sensitive in detecting nociceptive responses. Still, the relatively low specificity may increase the risk of false-positive detections. In this context, evaluating alpha-band suppression during PTC may help guide analgesic titration under general anesthesia.

In the present study, hemodynamic responses during short tetanic stimulation were significantly associated with low remifentanil concentrations. This aligns with previous research indicating that adequate analgesia can mitigate the nociceptive effects of short-tetanic stimulation.9,44 Furthermore, low body weight emerged as another risk factor for nociceptive response to short tetanic stimulation. Although the initial current intensity is set at a supramaximal level to produce a maximum transmission signal to the muscle, the current density dictates the electrical impact, which varies with the individual’s size or cross-sectional area in contact with the current source.48 This suggests that high current density may have the potential to induce nociception in underweight patients receiving tetanic stimulation. Additionally, our subgroup analysis employed a clinically relevant cutoff of 1.0 ng·mL−1 based on previous literature,9,11 which closely matched the median concentration observed in our study (1.014 ng·mL−1), ensuring balanced subgroup sizes. Logistic regression also suggested a similar optimal cutoff (1.108 ng·mL−1) for distinguishing responders from nonresponders. These findings indicate that maintaining remifentanil concentrations above this level may help reduce nociceptive responses during neuromuscular monitoring.

A recent guideline recommends monitoring the depth of neuromuscular blockade in patients receiving neuromuscular blocking agents during surgery.49 Monitoring PTCs is valuable for evaluating deep or intense neuromuscular blockades unresponsive to TOF stimulation, aiding in precisely titrating neuromuscular blocking agents. Nevertheless, the short tetanic stimulation used in PTC could be stronger than the surgical stimulus itself, depending on the type of surgery and the depth of anesthesia maintained. In less painful procedures, such as the ophthalmic or otolaryngologic surgeries in this study, the surgical stimuli are relatively mild compared with abdominal surgeries. Consequently, there may be a tendency to maintain lower levels of analgesics or to rely solely on hypnotics without administering analgesics. To prevent nociceptive responses induced by short tetanic stimulation in these surgeries, anesthesia providers must ensure adequate analgesia during PTC monitoring to optimize patient comfort and safety.

Our findings have important clinical implications for anesthetic management during procedures requiring PTC monitoring. Identifying low remifentanil concentrations and low body weight as risk factors suggests that these patient characteristics should be considered when determining analgesic requirements. Particularly in patients with low body weight, anesthesiologists might need to adjust either the stimulating current or provide additional analgesia to prevent nociceptive responses during PTC monitoring.

Our study has some limitations. First, owing to its retrospective nature, there may be some unavoidable biases. Nevertheless, to reduce potential confounding, we analyzed only the first short tetanic stimulation following tracheal intubation, limiting the impact of unrecorded interventions and avoiding complexities arising from repeated measurements. Although some patients may have been exposed to unrecognized stimuli during the surgical preparation phase, ophthalmic or otolaryngologic procedures generally involve minimal stimulation during this interval. The use of standardized anesthesia protocols and the consistent physiologic responses observed across a large sample (N = 732) enhance our findings’ internal validity. Nevertheless, prospective studies are needed to further validate these results. Second, because intravenous anesthetics have EEG profiles that differ from those of inhalational anesthetics,50 we excluded patients receiving total intravenous anesthesia, which may limit the generalizability of our findings. Third, although we identified alterations in hemodynamic and EEG band power following short tetanic stimulation, we did not assess the impact of these changes on clinical outcomes. Further studies are warranted to investigate potential implications for patient outcomes. Lastly, although not statistically significant, potential pharmacodynamic interactions between inhaled anesthetics and remifentanil cannot be completely excluded. Future prospective studies are warranted to explicitly explore these interactions.

In conclusion, our study shows that short tetanic stimulation during PTC monitoring can induce nociceptive hemodynamic responses, as evidenced by hemodynamic changes and EEG band power changes. These nociceptive changes were significantly associated with low remifentanil concentration and body weight. While our findings suggest an association between remifentanil concentrations and nociceptive response, prospective studies are needed to establish an optimal analgesic protocol during PTC monitoring, considering both efficacy and patient safety.