This nerve stimulator has a supramaximal stimulus frequency of 0.1–1.0 Hz. Its clinical value is limited. However, it may be useful for baseline assessment of neuromuscular function before NMBA administration. A single twitch was used to determine the time to the onset of neuromuscular blockade or to assess the status of the depolarizing NMB.

This is the gold standard for NMB monitoring. TOF provides information about the depth of NMB and the degree of recovery after reversal. TOF stimulation involves delivering a train of four electrical stimuli to a peripheral nerve, observing the evoked muscle responses, and measuring the amplitude of the resulting muscle twitch. The stimulation pattern consists of 4 twitches at a frequency of 2 Hz. A stimulation-free interval of at least 10 s is allowed between successive TOF stimulation patterns. The loss of the fourth response is indicative of 75–80% NMB. Sufficient NMB for surgical procedures is maintained until the reappearance of 2–4 responses. TOF count is the number of twitches elicited before fading, whereas TOF ratio (TOFR) is the ratio of the fourth to the first twitch. A TOF count of 0 indicates a deep blockade. A TOFR of 1 indicates full recovery, a TOFR of 0.7 is suggestive of adequate diaphragmatic recovery, a TOFR of > 0.9 indicates adequate pharyngeal muscle function, and a TOFR of 0.8 or less indicates the need for reversal [12]. A TOFR of 0.7 at the adductor pollicis muscle demonstrates satisfactory recovery of neuromuscular function. However, this NMB level is associated with the subjective symptoms of profound weakness [13] and objective signs of upper respiratory muscle and swallowing dysfunction [14,15]. The current standard for acceptable strength recovery is a TOFR of at least 0.90 in the adductor pollicis muscle. Responses to TOF stimulation may be evaluated subjectively (qualitatively) with direct visual observation and counting of muscle twitches following stimulation with a PNS. It can also be assessed objectively (quantitatively) by measuring the number of twitches in the TOF sequence (TOF count or TOFC), or by measuring the twitch height of the first TOF twitch (T1), the height of the 4th twitch (T4), and calculating the T4/T1 ratio or TOFR (Table 1) [2].

Monitoring the TOF response following the administration of NMBAs remains essential in guiding the timing of redosing and evaluating the efficacy of NMB reversal [16,17].

High-frequency (50–200 Hz) stimulation is applied for 5 s. A fading effect is observed with incomplete NMB recovery. The sensitivity and specificity of TS in detecting residual curarization are 70% and 50%, respectively [12].

This technique is used to assess deep NMB when TOF responses are absent. In other words, it is a tactile and visual evaluation of deep non-depolarizing NMB that does not respond to TOF. PTC involves the application of a tetanic stimulus, followed by a single nerve stimulus [12]. TS of 50 Hz for 5 s followed by 1 Hz supramaximal stimulation after a gap of 3s, is applied. The number of twitches elicited after a tetanic stimulus indicates the degree of NMB. Ideally, the PTC should be zero if a very deep NMB is desired. When the return of TOF is imminent, 5–7 responses are detectable.

This method is more sensitive than TOF stimulation for detecting residual NMB. DBS involves delivering two bursts of electrical stimuli at 50 Hz with an interval of 750 ms to a peripheral nerve and observing the evoked muscle responses. Bursts consist of 2–3 impulses, combined with impulse series 3/3 and 3/2. Fading of the second impulse series compared to the first one indicates incomplete NM recovery and is comparable to a TOF of < 0.6. DBS is more sensitive for the tactile evaluation of residual blockade [12].

TOF and PTC are the most useful methods for detecting deep and moderate NMBs (Table 1 and Fig. 1).

EMG measures the electrical activity of muscles and provides a real-time assessment of NMB. Unlike TOF stimulation, EMG provides continuous monitoring of NMB, allowing for the real-time assessment of muscle relaxation. However, EMG requires specialized equipment and expertise, making it less widely used than TOF stimulation [21-23].

Although not commercially available, every new device is compared to MMG. MMG is the gold standard of historical importance and requires careful calibration [21].

The TOF-Watch (Organon) was the first device to be widely used in clinical practice. It has been evaluated against the ‘gold standard’ MMG. However, it is no longer commercially available. AMG measures the acceleration of muscle movement, providing a more objective NMB assessment than qualitative TOF stimulation using nerve stimulators. AMG is the most widely used NMM, with the de facto standard of clinical care, is easy to handle, and is suitable for any free-moving muscle. AMG objectively measures the response to neurostimulation using a transducer fixed to the muscle of interest. Traditionally, standard electrocardiogram (ECG) electrodes are placed over the ulnar nerve and acceleration of the adductor pollicis muscle is measured. This configuration is very similar to employing a PNS in the hand, except for the additional transducer fixed to the thumb, foot (flexor hallucis brevis), and face (orbicularis oculi/corrugator supercilii), although not preferred or recommended [4,12,21,24-26].

For accurate measurements, the thumb must be allowed to move freely, and when the arms are placed under surgical drapes and are inaccessible during surgery, the NMM may not be accurate. Two or three serial TOF measurements at 15-s intervals should always be taken before deciding on an action (e.g., need for top-up doses, determining block level, and ensuring recovery after reversal).

Unlike the MMG and EMG, the baseline TOF ratio often exceeds 1.0 (100%), with some values reaching as high as 1.4 (140%). This is known as ‘reverse fade,’ and its cause is not fully understood, but it might be due to the thumb’s elastic recoil not going back to the baseline after each TOF stimulus. Therefore, AMG devices must be set to a baseline (supramaximal) value before an NMB and adjusted to reach a target recovery ratio of 0.9. For instance, if the baseline value is 1.2, a recovery ratio of 0.9 would need a measurement of 1.08. To avoid complications after surgery, recovery to at least 0.95 is necessary with AMG, and the European Society of Anesthesiology and Intensive Care (ESAIC) guidelines advise aiming for 1.0 when using uncalibrated ratios. Newer AMG devices have improved accuracy as they utilize sensors that measure movement in three directions, accounting for thumb movements in response to ulnar nerve stimulation. Some manufacturers assert that their products do not require calibration. In practical terms, the TOFR should be close to 1.0 when using AMG acknowledging that even with this level of recovery, the majority (> 75%) of postsynaptic receptors may remain blocked. Nevertheless, AMG monitors are readily accessible, easy to apply and operate. Importantly, a substantial body of evidence has demonstrated that they outperform clinical and qualitative recovery methods based on PNS [4].

With AMG, the TOFR overestimation is at least 0.15, with a baseline TOFR of > 1.0. Classic AMG options include the TOF-Watch^R (Organon), Infinity Trident NMT Pod^R (Drager), 3D AMGs like TOFscan^R (Drager Technologies), Stimpod NMS 450^R (Xavant Technology), and Mindray NM transmission transducer^R (Mindray Co.) [21,25,26].

KMG is closely related to AMG as a monitoring modality. KMG monitoring includes a piezoelectric sensor placed in the groove between the thumb and index finger, which bends when the APM contracts following ulnar nerve stimulation. Although it is easy to use, it is only used for the ulnar nerve adductor pollicis muscle group. Additionally, free thumb movement and good strip placement between the fingers are required [20].

Previous reports demonstrated wide limits of agreement between MMG and KMG. Similar to the AMG, the KMG is dependent on the ability of the thumb to move freely during surgical positioning. Patient movement during emergence can also affect KMG monitoring, as does the repositioning of the sensor over the course of the perioperative period. Currently, the only available KMG-based device is incorporated into anesthesia workstations (e.g., Datex Ohmeda NMT^R) [20,21,25].

The advantages and disadvantages of the quantitative monitoring methods are summarized in Table 2.

Quantitative TOF monitoring has not been used widely in infants and children primarily because of the lack of effective equipment. In a recent study, a novel commercially available EMG-based monitor known as the TetraGraph™ (Senzime AB) and a novel pediatric array known as the TetraSens™ (Senzime AB) Pediatric, with a pediatric-sized self-adhesive sensor, had been assessed (Fig. 2) [25,27,28]. The TetraGraph™ is a commercially available EMG-based TOF monitor, which provides electrical stimulation over a peripheral nerve, and then, directly measures the amplitude (muscle action potential) of the evoked responses of the innervated muscle, providing a quantitative measurement of the muscle response to the stimulus. The measurement and quantification of the EMG response eliminates the subjective evaluation required for visual observation of twitches. Clinical studies have also demonstrated that quantitative measurements using the TetraGraph provide a more sensitive and reproducible measure of the degree of NMB and recovery than visual measurements using a PNS [24,29]. The TetraSens^TM sensor is indicated for pediatric patients younger than 8 years of age. It is able to monitor EMG-based neuromuscular transmissions in infants and children in whom AMG and/or visual observations of the TOF response may not be possible (Fig. 2) Automatic detection of neuromuscular stimulating parameters, such as supramaximal current intensity level and baseline amplitude of the muscle action potential, is possible in pediatric patients including those weighing less than 15 kg or in instances where there is limited access to the extremity being monitored [28]. The application of this novel sensor in infants and children weighing less than 10-15 kg has led to consistently successful NMM, which was previously deemed not possible. However, a difference in the recovered amplitude should be considered (the recovered amplitude is statistically less in patients ≤ 15 kg). This may be related to differences in the maturation of neuromuscular transmission [29], which has been previously noted when evaluating TOF using an AMG with a force displacement transducer [20].

Quantitative NMB monitors, such as the Tetragraph™ (Senzime AB), Twitchview (Seattle), and TOFScanR (Drager Technologies), are able to display PTC and TOFR in real-time. When TOF is zero, AutoPTC is activated. TOF-Watch SX (Organon) is as accurate as TOFScan when calibrated but may overestimate the TOFR. In contrast, the TOFScan is 3D, easily understandable and no calibration is required [30].

As previously mentioned, AMG necessitates that the target muscle (typically the thumb) move freely for response measurement or be visible for subjective assessment. This requirement may limit its use in procedures in which the patient’s arms are restricted by surgical drapes or are not freely visible. The risk of postoperative residual NMB has been shown to be 5-fold higher when a PNS and the supramaximal current are not determined [31]. Notably, with AMG NMM, the baseline TOFR may be > 100% [32-34]. Considering this falsely elevated baseline, the recovering TOFR must be normalized to the starting baseline ratio to avoid inaccuracies when assessing NMBA reversal and the degree of residual NMB. This inaccuracy has not been observed with EMG-based technologies like the TetraGraph™. When compared to visual monitoring, the TetraGraph™ evaluates fade by calculating the TOFR, thus allowing for intraoperative titration of additional NMBA doses, as well as documentation of effective antagonism (TOFR > 0.90). This aims to prevent residual paralysis and its clinical consequences [10,11]. Although potential or residual NMB should be assessed in the post-anesthesia care unit (PACU), its clinical impact has not been evaluated in studies thus far, as it is very difficult, and possibly ethically questionable, to apply NMM in awake patients.

Most pediatric pharmacokinetic and pharmacodynamic studies conducted before the mid-1990s utilized either MMG (Grass FT-03 or Grass FT-10 force–displacement transducer, Grass Instrument Co.) or EMG (Relaxograph, Datex). MMG is still considered the research standard for NMM. However, recent evidence has demonstrated that EMG correlates well with MMG, and is reliable, reproducible, and easier to use in clinical research [4,23]. Importantly, MMGs are no longer manufactured for clinical use. However, reference MMG-based monitors are available for validating new EMG-based monitors [23]. AMG, such as the TOF-Watch SX (Organon), has been used in pediatric studies. The TOF-Watch was the first device widely used in clinical practice. It has been evaluated against the ‘gold standard’ (MMG). AMG use in pediatric patients poses similar limitations as in the adult population including TOFR overestimation (inverse fade) when compared with MMG and EMG and the “staircase” phenomenon associated with ST stimulation [35]. AMG monitors also require a significant amount of time (5–10 min) for stabilization of the baseline signal, although a 5 s tetanic stimulation may prevent the staircase phenomenon and shorten the signal stabilization requirement [29]. Neonates and infants, aged less than 1 year, may require a manual increase in the gain of the transducer to obtain a first twitch in the TOF sequence (T1) of 100% [25].

Recent reports have described the successful use of EMG in pediatric patients [36-38]. There currently are no studies that have determined the supramaximal current requirements as a function of age, but in pediatric patients weighing 20–60 kg, the current intensity at a pulse width of 0.2 ms was 30 mA in 3%; 40 mA in 42%; 50 mA in 28%; and 60 mA in 22% of patients, while the average baseline amplitude of the response was 7.5 mV [38]. Minimum current amplitudes necessary for the visual detection of contractions are approximately 20 mA (with a range of 10–45 mA), which is similar to those in adults [39]. The small sizes of pediatric patients impose technical challenges regarding appropriate equipment. Lead placement and electrode size may affect the current density and, therefore, the required charge for a supramaximal response. Temperature changes can also affect the EMG electrical signal amplitude, but to a lesser extent than when using MMG or AMG [4].

Properly cleansed skin, rubbed with an abrasive, is essential prior to placing surface electrodes for supramaximal stimulation. The skin surface should also be allowed to dry completely before electrode placement [4]

The correct placement of the electrodes is important to ensure that the nerve is stimulated with the selected current (Fig. 3). The size of the conducting area of the stimulating electrode is also important. With a large conducting area, it may be difficult or impossible to obtain supramaximal stimulation because a sufficient current density cannot be obtained in the nerve underlying the stimulating electrode. Typically, the contact area of the stimulating electrode is 7–11 mm in diameter. The distance between the centers of the two electrodes is 3–6 cm. Finally, although the polarity of the stimulating electrodes is also important, it is recommended that the negative electrode be placed distally to optimize the nerve stimulation response [3,36].

1. Pediatric-sized nerve-stimulating electrodes made of silver/silver chloride (Ag/AgCl) are utilized. The negative electrode is always distal to the positive electrode [33]. An alternative position is to place the positive electrode on the ulnar groove at the elbow to improve ulnar nerve depolarization. Electrodes are placed on the supinated palm while extended passively [4].

2. Two electrodes should be placed along the ulnar nerve [2].

3. The negative (black) electrode is positioned distal to the styloid process of the radius [2,38].

4. The arm should be fixed to an arm board to minimize muscle movements (e.g., adductor pollicis brevis).

5. The adductor pollicis brevis muscle originates from two heads (oblique head from the second and third metacarpal bones, and transverse head from the third metacarpal bone) and inserts at the base of the proximal phalanx of the thumb. Contraction of the adductor pollicis brevis brings the tip of the thumb to the center of the palm. However, adjacent muscles, such as the opponens pollicis and flexor pollicis brevis can also contribute to similar movements. Due to the shallow skin-to-nerve and nerve-to-nerve distances in pediatric patients, using a standard ‘3 cm’ distance between the positive and negative electrodes may inadvertently stimulate the median nerve, which innervates the opponens pollicis and flexor pollicis brevis. This distance determines the penetration depth. With the electrodes being relatively far apart in the relatively short pediatric forearm, nearby muscles may also react. Strapping prevents the movement of only four fingers, not the thumb. The opponens pollicis and flexor pollicis brevis cannot be restricted to mere strapping. Moreover, the deep parts of the opponens pollicis and flexor pollicis brevis in 20% of the population are innervated by the ulnar nerves C8 and T1. Erroneous extra-apposition of the thumb due to the mixed effect of unwanted muscle movement is likely to occur in pediatric patients with smaller hands and a greater proximal nerve-to-nerve distance. Since this may cause unwanted acceleration, normalization is required when assessing 3D acceleration in children (Fig. 4) [38].

6. To establish a baseline NMB level before administering NMBAs, calibration should be performed before NMBA administration but not after induction.

7. Individual differences in distribution volume, muscle mass, clearance of NMBAs, and age-dependent maturation of neuromuscular junctions contribute to differences in the initial TOFR and normalization adjusts the inherent TOFR.

8. While changes in core temperature influence the pharmacodynamics and pharmacokinetics of NMBAs, variations in peripheral temperature at the NMM site can also impact the response to nerve stimulation. Neonates are highly sensitive to changes in body temperature, which can affect neuromuscular function and subsequently affect monitoring accuracy. Hypothermia can potentiate the effects of neuromuscular blocking agents, leading to increased sensitivity and prolonged blockade duration. However, hyperthermia can also result in drug resistance. Therefore, maintaining stable body temperature is crucial for reliable NMM in neonates. The temperature should be maintained constant; a central temperature above 35°C and peripheral temperature at the monitored muscle above 32°C is recommended [4,39-42].

9. For a meaningful comparison between technologies (AMG, EMG, and MMG), the AMG monitor must be calibrated. For AMG, the final recovery TOFR must be normalized to the baseline ratio unless tetanic pre-stimulation is performed [4,30].

10. To expand the validity of the TOFscan to infants and neonates, a smaller pediatric hand sensor is required [38].

11. The application of a 5-s, 50-Hz tetanic stimulation prior to calibration may prevent the staircase phenomenon and shorten the signal stabilization period [4,28].

12. A preload can be considered for neonates and infants; however, a clear description of the technique must be presented when a study is planned [4].