14 October 2024: Clinical Research
Evaluation of Neuromuscular Blockade: A Comparative Study of TOF-Cuff on the Lower Leg and TOF-Scan on the Ulnar Nerve During Mivacurium Anesthesia
Paweł Radkowski 12ABCDF*, Jakub Ruść 23BCDEF, Mariusz Kęska 12BDEGDOI: 10.12659/MSM.945227
Med Sci Monit 2024; 30:e945227
Abstract
BACKGROUND: To evaluate neuromuscular monitoring during anesthesia with mivacurium, this study assessed the correlation between measurements of TOF-Cuff® placed on the lower leg and stimulating the tibial nerve and TOF-Scan® values from the adductor pollicis muscle. Additionally, systolic (SBP) and diastolic (DBO) blood pressure measured in both locations were compared.
MATERIAL AND METHODS: Twenty-six patients participated in this observational clinical trial. The TOF-Cuff® was placed on the lower leg and the TOF-Scan® was placed on the thumb. Train-of-four (TOF) values were recorded simultaneously by both devices at 30-second intervals before intubation. Measurements continued every 5 minutes until extubation. Bland-Altman analyses compared TOF values obtained from the 2 devices.
RESULTS: Time to onset and relaxation time did not differ significantly; the number of patients presenting a lack of blockade despite TOF=0 was also concordant. The time from the last dose of mivacurium to TOF ratio >90 was shorter on the leg than on hand (median 20 [5-28, 0-65] min vs 30 [20-35, 0-60] min, p=0.025). The median (range, interquartile range) difference between measurements was: 11.6 (-41 to 45, 2-19) for SBP and -8 (-28 to 26, -15 to -4) for DBP at baseline (p=0.0495); 5 (-53 to 55, -2 to 9) for SBP and -11 (-45 to 29, -19 to -5) (p=0.0017) for DBP during the blockade.
CONCLUSIONS: Time-to-onset and SBP are comparable between these 2 methods, in contrast to time-to-recovery and diastolic blood pressure, and this should be considered in case of the inability to apply the TOF-Cuff on the leg.
Keywords: Airway Extubation, Intubation, mivacurium, Neuromuscular Monitoring
Introduction
Non-depolarizing neuromuscular blocking agents (NMBAs) are commonly administered during anesthesia or in intensive care units to facilitate endotracheal intubation, enhance ventilation, and reduce postoperative hoarseness but despite those advantages, they can also lead to respiratory complications that impact clinical recovery [1] and therefore must be strictly monitored [1,2].
Neuromuscular blockade monitoring methods may involve clinical assessment (head and leg lift test, grip strength, tongue depressor test), which is often unreliable, or peripheral nerve stimulation with different principles and different patterns of stimulation [3]. Ulnar nerve palm mechanomyography (MMG), once considered the “gold standard” for assessing muscle relaxation during general anesthesia in clinical trials, is no longer available commercially [4]. The same applies to phonomyography (PMG) which is based on measuring the emitted low-frequency sound of sliding muscle fibers [3]. Electromyography (EMG), which measures compound muscle action potentials evoked by neurostimulation, may interfere with other electrical equipment [3]. Kinemyography (KMG), based on the distortion of a piezoelectric film sensor proportional to the force of thumb contraction, is available only in modular form [3].
Therefore, the motor response is evaluated usually by measuring thumb acceleration [1]. Acceleromyography devices serve as standalone quantitative monitors [4]. These devices utilize piezoelectric sensors to measure muscle or finger acceleration [1]. Initially, monitors assessed acceleration in a single plane (e.g., TOF-Watch®) [5]. Advanced versions, like the TOF-Scan®, employ three-dimensional sensors [5] attached to the thumb, big toe, or brow muscle, capturing acceleration across multiple planes [3,6]. Additionally, adhesive electrodes are positioned over the ulnar nerve, tibial nerve, and the root of the facial nerve [3]. The sensor may be placed in many different locations but clinicians routinely use the response of the adductor pollicis muscle to electrical stimulation of the ulnar nerve as a standard method for monitoring neuromuscular blockade [1]. Typically, an electrical stimulus is applied via adhesive electrodes placed on the medial lower arm over the ulnar nerve, resulting in nerve stimulation; the motor response is then quantified in terms of acceleration [6].
The most frequently employed stimulation method is the train-of-four (TOF), introduced by Ali and Gray in 1970, which compares motor responses elicited by the fourth and first stimuli [3]. It involves delivering 4 supramaximal stimuli at a frequency of 2 Hz [3]. The resulting TOF ratio (the ratio of the fourth twitch height [T4] to the first [T1]) assesses the degree of neuromuscular blockade [3]. It ranges from 100% (indicating no effect of neuromuscular blocking agents) to 0% (no muscle reaction to the fourth stimulus). A TOFratio ≥90% signifies recovery from the effects of NMBAs, while a TOFratio <90% indicates residual blockade [3]. A TOFR ≥90%, measured at the adductor pollicis muscle after ulnar nerve stimulation, is recommended for confirming recovery [7,8].
Another comparable tool, based on compressomyography and validated using mechanomyography, is the TOF-Cuff® [3,6]. This technique is based on the measurements of the pressure change in a modified non-invasive blood pressure cuff due muscles’ contraction evoked by brachial plexus stimulation [6]. Integrated electrodes within a blood pressure cuff monitor muscle activity in the upper arm during plexus brachialis stimulation or in the leg, targeting the tibial nerve [6]. The device’s significant advantage is its capability to take measurements regardless of the patient’s position and its autopilot mode, which senses changes in the patient’s position and automatically begins measuring vital signs [6]. It is suitable for use during surgical procedures where the arms are tucked, as it does not require a freely moving thumb for measurements [6]. Combining a non-invasive blood pressure monitor with a neuromuscular blockade detection monitor, it reduces the time needed to set up equipment, which is particularly beneficial during urgent caesarean sections under general anesthesia [6].
To date, only 3 papers by other authors have been published comparing the results obtained by the 2 methods on different limbs. All involved a different muscle relaxant (atracurium) and involved comparisons of: upper arm vs opposite upper arm [9], ulnar nerve (wrist) vs lower leg [10], and upper arm vs ulnar nerve (thumb) [5]. Although the choice of measurement site is arbitrary, individual muscles differ in their response to stimulation [11], because muscles have varying sensitivities to NMBAs [4,6]. In ascending order these are: diaphragm, corrugator superscilii, vocal chord muscles, orbicularis occuli muscles, abdominal muscles, adductor pollicis muscle, genioglossus muscle, masseter muscle, and pharyngeal muscle [6]. Furthermore, equivalence studies are sometimes divergent. For example, in the first clinical trial, the agreement between TOF-Cuff and MMG was comparable to other methods when compared to MMG [12] whereas in a later clinical trial, it was observed that TOF-Cuff tended to overestimate the MMG-derived TOFR by 20% during the final recovery phase [13].
The locations where AMG sensors can be placed are numerous [6]. From a technical feasibility point of view, the compressomyography device can be placed on both the upper limb and the lower limb. However, there are few comparisons assessing how the location of the measurement affects the result. Due to scarce literature in this field, we conducted a complex, multicohort clinical study aimed at finding an alternative method of measurement that is feasible for patients who, for various reasons, cannot be measured at a standard site. In the previous papers describing different cohorts from the same experiment, we described TOF-Cuff® vs TOF-Scan® placed on the eyelid [14] and TOF-Cuff® vs TOF-Scan® placed on the thumb [data not published yet]. In this article, we compare TOF-Cuff® placed on the leg vs TOF-Scan® placed on the ulnar nerve.
Material and Methods
BIOETHICS:
The study adhered strictly to the principles of the Helsinki Declaration. The patients gave informed consent to participate in this study. It commenced after obtaining approval from the Bioethics Commission at the Faculty of Medicine of Collegium Medicum of the University of Warmia and Mazury in Olsztyn (Approval No. 10/2021). The trial was registered on
STUDY DESIGN:
At the Olsztyn Regional Specialized Hospital, a cohort of 26 patients meeting specific criteria was assembled for this study: individuals aged between 18 and 75, with a body mass index (BMI) ranging from 17 to 35, categorized under ASA physical status I–III, and scheduled for a surgical procedure. Exclusion criteria included pregnancy, breastfeeding, urgent surgery needs, the American Society of Anesthesiologists (ASA) physical status exceeding III, neuromuscular disorders, polyneuropathy, diabetes, substance abuse, familial history of malignant hyperthermia, and allergies to propofol, fentanyl, or mivacurium.
ANESTHESIA PROCEDURES:
Standardized anesthesia protocols were applied uniformly to all patients. Monitoring encompassed electrocardiography, non-invasive blood pressure measurement on the upper extremity, pulse oximetry, and capnography. A TOF-Scan® (Dräger; Germany) sensor was affixed to the thumb, with electrodes aligned along the ulnar nerve near the wrist, spaced 2 to 5 cm apart. Following skin preparation, a TOF-Cuff® (Viridian, Poland) was placed on one leg (without the TOF-Scan® sensor) per the manufacturer’s instructions, targeting tibial nerve. The train-of-four stimulus amplitude was set at 40 mA. Anesthesia induction comprised fentanyl, propofol, lidocaine (if epidural analgesia was not administered), dexamethasone, and mivacurium at 0.2 mg/kg. Sevoflurane at 1.0 MAC concentration maintained anesthesia.
Intubation was indicated by a TOFratio of 0 on the TOF-Cuff®. Clinicians could administer additional mivacurium doses to achieve complete neuromuscular recovery post-surgery. Hypotension was managed with ephedrine or fluid boluses, while hypertension was addressed by adjusting sevoflurane concentration. Supplementary fentanyl doses were administered as needed, and ventilation was regulated to maintain end-tidal carbon dioxide between 35 and 45 mmHg. Ondansetron was given 30 minutes before the surgery’s conclusion. Post-surgery, neostigmine (40 μg/kg) and atropine (8 μg/kg) were administered to ensure complete neuromuscular function recovery in patients not spontaneously reaching a TOFratio ≥0.9.
OUTCOME MEASURES:
After losing consciousness and cessation of mivacurium administration, TOFratio measurements commenced simultaneously on the adductor pollicis and lower extremity in each patient. Measurements occurred every 30 seconds until intubation, then every 5 minutes until extubation. Extubation occurred when the leg TOF-Cuff® reading exceeded 0.9, indicating readiness for independent breathing. Intubation/extubation times, mivacurium doses, and side effects were documented. Intubation difficulty was rated on a scale from 1 to 4, and various time intervals related to neuromuscular block were measured.
Blood pressure measurement was conducted on the leg using TOF-Cuff and on the arm where TOF-Scan was placed using the Drager Infinity Delta XL. Blood pressure was measured at baseline (second 0) and intraoperatively at regular intervals of every 5 minutes starting from the 600th second, comparing pairs of measurements made by both devices simultaneously. Systolic (SBP) and diastolic (DBP) blood pressure values were analyzed separately.
STATISTICAL ANALYSIS:
The sample size was based on previous clinical studies by other authors, which ranged from 20–30 subjects, resulting in a power >95% in post-hoc analysis. Continuous variables were presented as median, interquartile range, and range. Wilcoxon test assessed differences between paired measurements. Spearman correlation coefficient examined continuous variable relationships. Kaplan-Meyer curve was used to present the time to onset and log-rank test compared curves for both methods. Bland-Altman test validated methods. Additionally, for each patient, the Spearman correlation coefficient was calculated for a series of measurements generated by both devices; then, individual Spearman R values were presented in the figure as a distribution. TOF-Scan® correction was estimated by calculating the TOF-Cuff®: TOF-Scan® time ratio. The discrepancy between clinical symptoms and measurements was analyzed, along with false negative measurements between methods. Statistical significance was set at p<0.05. Data were analyzed using Statistica 13.0 (Tibco) and Microsoft Excel.
Results
CLINICAL CHARACTERISTICS OF THE PARTICIPANTS:
The study included 26 patients (18 [69.8%] men, 8 [30.8%] women), with a median (range, interquartile range [IQR]) age of 54 years (22–74, 34,5–66) and BMI of 26.0 (18.8–33.1, 23.7–29.8). Eight (30.8%) patients were categorized as ASA stage I, 16 (61.5%) as ASA II, and 2 (7.7%) as ASA III. All patients underwent surgeries for laryngological indications (9 [34.6%] microlaryngoscopy, 7 [26.9%] septoplasty, 2 [7.7%] chordectomy, 2 conchoplasty, 1 [3.8%] septoplasty+functional endoscopic sinus surgery (FESS), 1 lymph node biopsy, 1 rhinoplasty, 1 tonsillectomy, 1 neck cyst removal, 1 unspecified). Most intubations (17 [65.4%]) were rated as very easy, 3 (18.8%) as easy, 4 (15.4%) as rather difficult 2 not specified (7.7%). Adverse reactions included flash in 10 cases (38.5%). In 4 (15.4%) instances, patients were intubated despite a TOFratio >0 as assessed by TOF-Cuff. In 2 (7.7%) patients, vocal cord gapping remained closed despite a decrease in TOFratio to 0 as assessed by TOF-Cuff. Lidocaine was administered in 2 (7.7%) cases. Muscle block antagonists had to be used in 5 (19.2%) patients.
TIME TO ONSET OF NEUROMUSCULAR BLOCKADE:
In the time-to-event (onset) analysis, the median time of onset of hand muscle blockage was 210 s, while that of the leg muscle was 240 s (P=0.467; Figure 1). After 600 s, 2 (7.7%) patients did not reach neuromuscular blockade on the hand, 3 (26.7%) did not reach it on the leg, and one (3.8%) on both extremities (censored observations).
Spearman correlation between the time to onset in TOF-Cuff measurements and the time to onset in TOF-Scan measurements was significant (p<0.05) and equal 0.613. Due to the lack of normal distribution, we expressed the relationship between the results as the ratio of both measurements, indicating the ratio of the time taken to reach onset as measured by TOF-Cuff compared to the time taken to reach onset measured by TOF-Scan, thereby determining the factor by which the time measured by TOF-Scan must be multiplied to achieve a comparable result to that measured by TOF-Cuff (Table 1). The minimum value, successive deciles, and maximum for this correction factor were: 0.1, 0.5, 0.7, 0.9, 1.0, 1.0, 1.0, 1.2, 1.8, 2.5, 2.9 for TOF-Cuff/TOF-Scan ratio and 0.3, 0.4, 0.6, 0.9, 1.0, 1.0, 1.0, 1.2, 1.3, 2.0, 7.0, respectively. The Bland-Altman plot is presented in Figure 2A.
DURATION OF NEUROMUSCULAR BLOCKADE:
Among 26 patients, 9 (34.6%) were administered a solitary dose of mivacurium, whereas 17 (%) received a maximum of 7 additional doses. In the group of 9 patients who received only one dose, the relaxation times [in minutes] recorded using the TOF-Cuff versus the TOF-Scan method were as follows: 25.0 vs 43.5, 14.5 vs 10.5, 12.5 vs 10.0, 16.5 vs 16.5, 32.5 vs 11.5, 35.0 vs 19.0, 65.0 vs 22.0, 19.5 vs 19.5, 0.0 vs 5.0. The median value (IQR, range) for relaxation time on the leg was 15.75 (15.5–33.75, 0–65) minutes, and on the arm was 14.0 (10.25–20.5, 5–43.5) minutes. This difference was not significant (p=0.398).
In 2 patients, symptoms of preterm neuromuscular return were observed during the blockade period. In the first case, the operator noted closed vocal cords, while in the second case, the patient was swallowing. In both instances, both devices indicated TOFratio=0; the patients received an additional dose of mivacurium.
At minute 15, upon resumption of monitoring, a TOFratio=0 persisted in 20 out of 24 patients (83.3%) who had not previously received an additional dose of mivacurium, according to TOF-Cuff, and in 21 patients (87.5%) according to TOF-Scan. Two patients (8.3% of those who did not receive an additional dose) showed concordant results of TOFratio >0 using both methods. Sixteen patients (66.7%) yielded concordant results of TOFratio=0, while 3 patients (12.5%) exhibited a result of TOFratio >0 solely according to TOF-Cuff, and 2 patients (8.3%) solely according to TOF-Scan; one patient lacked a TOF-Cuff measurement, thus concordance could not be determined.
The correlation coefficient value for TOFratio=0 times measured by both devices was 0.738 (p<0.05) among those who did not receive an additional dose of mivacurium throughout the blockade period, and 0.415 (p<0.05) among those who received at least one additional dose.
The correlation coefficient value for TOFratio<90 times measured by both devices was 0.717 (p<0.05) among those who did not receive an additional dose of mivacurium throughout the blockade period. Among those who received at least one additional dose, the correlation coefficient value was 0.358 and was not statistically significant.
:
The time from the last administration of mivacurium to TOFratio >90 was shorter for the muscles of the lower extremity compared to those of the hand (median 20 [5–28, 0–65] min vs 30 [20–35, 0–60] min, p=0.025). The Bland-Altman plot is presented in the Figure 2B. The Spearman correlation coefficient for time to recovery assessed using both methods was 0.4 (p<0.05); however, after excluding 2 outlier observations, the correlation ceased to be statistically significant.
Time to recovery according to TOF-Cuff was correlated with age (R=0.471, p<0.05) and ASA classification (10 [5–17.5, 0–20] in stage I patients vs 25 [17.5–41.24, 0–70] in stage II patients [p=0.016]), but not with BMI. It was also correlated with time to onset according to TOF-Cuff (R=−0.597, p<0.05) and relaxation time after the initial dose (R=0.746, p<0.05).
Time to recovery according to TOF-Scan was not correlated with age or BMI but was correlated with time to onset according to TOF-Scan (R=−0.406, p<0.05), while independence was observed with relaxation time after the initial dose (R=0.361, not significant [NS]).
Similar to the time to onset, we provided the time to muscular return ratio (Table 2). The minimum value, successive deciles, and maximum for the correction factor were 0.0, 0.1, 0.3, 0.6, 0.7, 0.8, 1.0, 1.1, 1.3, and 1.8 for the leg/hand ratio, and 0.5, 0.7, 0.9, 0.9, 1.2, 1.3, 1.7, 2.0, 3.0, and 9.0 for the hand/leg ratio, respectively.
SYSTOLIC AND DIASTOLIC BLOOD PRESSURE:
The median (range, IQR) SBP at time 0 was 137.5 (101–183, 126–147) mmHg on the arm and 142 (106–196, 136–156) mmHg on the leg. During the blockade period, the corresponding values were 107 (64–191, 94–121) mmHg and 112 (52–198, 98–126) mmHg, respectively. The median (range, IQR) DBP at time 0 was 80.5 (52–111, 74–88) mmHg on the arm and 74.5 (49–88, 67–80) mmHg on the leg. During the blockade period, the corresponding values were 70 (37–123, 58–80) mmHg and 56 (30–105, 47–68) mmHg, respectively. The analogous values for differences (Cuff–Scan) between measurements were: 11.6 (−41 to 45, 2–19) for SBP at time 0; −8 (−28 to 26, −15 to −4) for DBP at time 0; 5 (−53 to 55, −2 to 9) for SBP during the blockade; −11 (−45 to 29, −19 to −5) for DBP during the blockade. The difference between SBP measurements at time 0 was statistically significant (p=0.0495), as was the difference between DBP values (p=0.0017). The Bland-Altman plots for blood pressure measurements are illustrated in Figure 3A–3D.
The Spearman correlation coefficient between SBP values measured on the arm and leg during the blockade period was significant in 20 (76.9%) patients, insignificant in 5 (19.2%), and uncalculable in 1 (3.9%) due to lack of measurements. The Spearman correlation coefficient between DBP values measured on the arm and leg during the blockade period was significant in 13 (50.0%) patients, insignificant in 12 (46.2%), and uncalculable in 1 (3.8%) due to lack of measurements. The Spearman correlation coefficient between SBP and DBP values measured on the arm during the blockade period was significant in 21 (80.8%) patients, insignificant in 4 (15.4%), and uncalculable in 1 (3.8%) due to lack of measurements. The Spearman correlation coefficient between SBP and DBP values measured on the leg during the blockade period was significant in 10 (38.5%) patients, insignificant in 15 (57.7%), and uncalculable in 1 (3.8%) due to lack of measurements. The correlation coefficients varied individually; the distribution of significant correlations is presented in Figure 4. Among the correlation distributions depicted in this Figure, only the difference between the correlations of SBP and DBP on the arm and the correlations of DBP between limbs was statistically significant (p=0.0414).
Discussion
Our study revealed that the reliability of various parameters obtained using TOF-Scan placed on the adductor pollicis compared to TOF-Cuff placed on the leg is varied. Time to onset and SBP yield comparable results. This result is concordant with those obtained in a similar study by Dullenkopf et al 2020 [10]; the other studies did not assess blood pressure comparability. In contrast, time to recovery (and, consequently, relaxation time) was shorter on leg and DBP were significantly lower. Although individual muscles are known to differ in their response to NMBA, one would expect this response to be for both time to onset and time to recovery, as was the case in our previous work, in which we demonstrated a significantly shorter time to onset for TOF-Scan and significantly longer time to recovery for TOF-Scan when comparing TOF-CUF located on the upper arm and TOF-Scan located on the eyelid [14]. Also, a paper by Chau et al showed a lack of difference for both parameters after placing the devices on the same muscles of both upper limbs [9]. In contrast, the Markle 2020 publication [5], which compared a TOF-Cuff placed on the upper arm with a TOF Scan placed on the ulnar nerve (thumb) after atracurium application, reported a longer both time to onset and time to recovery on the TOF Scan device (Table 1). It would therefore be difficult to conclude that the difference we observed only in time to recovery is a matter of a difference in the response of the plexus brachialis to NMBA. However, we have not found an alternative substantive explanation in the literature to explain this phenomenon. Rather, we are inclined to hypothesise that the cause is the size of the study sample resulting in a power insufficiently high to separate the curves shown in Figure 1.
Most commercially available devices yield consistent results regarding recovery, but there are reports of discrepancies in time-to-onset between different methods [1]. The issue of concordance between measurements using the TOF-Cuff and TOF-Scan devices has been previously addressed by other authors, but those studies involved a different NMBA, atracurium [5,9,10], and the authors who used rocuronium compared TOF-Cuff to TOF-Watch [15]. This is significant because mivacurium is a benzylisoquinoline while rocuronium, vecuronium, and pancuronium are steroidal NMBAs. Our clinical study, encompassing the previously described comparison of TOF-Scan on the corrugator supercilii with TOF-Scan on the forearm [14], and TOF-Cuff on the forearm with TOF-Scan on the adductor pollicis [in review], is the only one in which both devices were compared following mivacurium administration. Compared to our previous publication, this analysis demonstrated greater agreement in measurements regarding the onset of neuromuscular block. In the current analysis, time to onset was very similar regardless of the site and method of measurement in approximately half of the patients; the correction factor was close to 1 and exceeded 2 in only 3 cases, which significantly deviates from the values observed by us previously.
Among patients who received only one dose of mivacurium, the duration of blockade did not differ significantly statistically, although in some cases, discrepancies were clinically significant and amounted to several minutes. Patients who received additional doses did not differ in terms of BMI (analyzed as a continuous variable or after clinical categorization) or age from those who did not receive them. To some extent, they differed in gender: among 17 patients who received an additional dose, 14 (82.3%) were males, while among 9 patients who did not receive it, 4 were males (44.4%) (p=0.046). It is known that gender influences the metabolism rate of many xenobiotics, but this does not explain the lack of correlation between the upper and lower limbs. Therefore, in the collected data, we do not find a strong explanation for why, in the case of those who received additional doses, the correlation between limbs was significantly weaker for both the time of deep relaxation (TOFratio=0) and effective (TOFratio <90). Some insight into this issue may be provided by a publication comparing the sensitivity of the adductor pollicis to mivacurium in men and women [16]. According to the authors, this muscle differs in susceptibility to mivacurium-induced relaxation between genders, however, due to the small sample size (10 individuals of each gender), this hypothesis should be treated with caution because with such a small sample size, any factor related to individual variability could have distorted the results.
In contrast to time-to-onset, time to recovery from the last dose of mivacurium was significantly shorter on the lower extremity than on the hand, and the correlation was weak and diminished after excluding only 2 outliers. On the other hand, a similar phenomenon of faster recovery recording by the TOF-Cuff was noted by Markle et al [5] who, like us, were unable to explain it in the context of currently available knowledge. In our study, the difference between the medians was 10 minutes, but in individual cases, the difference ranged from −60 minutes to +30 minutes. For measurements on the lower extremity, age was a significant predictor (as expected [17]: higher age associated with longer time to recovery), ASA status (median longer by 15 minutes in stage II compared to stage I; there were too few patients in stage III to conclude), and indicators of drug onset speed: time to onset and relaxation time after the first dose. However, for measurements on the hand, the predictor of time to recovery was only time to onset, and the correlation strength was moderate at the border of weak. This suggests that when TOF-Scan on the hand is necessary, expectations based on patient response to the drug may be inaccurate, unlike expectations based on parameters observed on the lower extremity.
Arterial blood pressure monitoring during blockade is necessary because NMBAs cause a decrease in blood pressure [18]. In our study, the median SBP during the blockade period was lower by 30 mmHg compared to the pre-blockade period both on the arm and on the leg, while the median DBP was lower by 10.5 mmHg on the arm and by 18.5 mmHg on the leg. The difference in measurements between the leg and the arm was positive for SBP (with a median of 11.6 mmHg before blockade and 5 mmHg during blockade) and negative for DBP (with a median of −8 mmHg before blockade and −11 mmHg during blockade).
A meta-analysis of 887 articles comparing blood pressure measurements on the arm and leg in 9771 patients showed that in the general population, SBP value in supine position was 17.0 mmHg higher on the ankle than on the arm, but no difference was found for DBP [19]. Considering the above and assuming that TOF-Cuff measurement, being the gold standard validated invasive blood pressure measurement [20], is a more reliable value, it should be assumed that the SBP value measured on the arm may be elevated both before and during blockade, while the DBP may be underestimated both before and during blockade, and at the same time, the change in DBP value measured after NMBA administration may be underestimated on the arm. Furthermore, the correlation between SBP and DBP values on the limbs proved to be individually variable, although generally, the correlation between SBP values was quite high (comparable to the correlation between SBP and DBP measured on the same limb), but this did not apply to the correlation between DBP values across limbs, which was significantly smaller. This is another result indicating that DBP values measured on the arm are subject to greater error. On the other hand, a surprising finding was the difficult-to-explain lack of correlation between SBP and DBP measured on the leg, despite the significant correlation of these values on the arm, consistent with previous reports [21]. Dullenkopf et al, who conducted a similar analysis for patients receiving atracurium, did not show significant differences in blood pressure values between TOF-Cuff on the leg and TOF-Scan on the adductor pollicis, but they did not analyze blood pressure values split by SBP and DBP, but only collectively, which could have caused the lack of capturing this significance [10]. This is particularly important since the same numerical difference in DBP values is clinically more significant than the identical numerical difference in SBP values.
Our study has several limitations. Firstly, in our sample, 2 patients received lidocaine additionally, which may enhance the effects of certain NMBAs [18]. Although a meta-analysis of clinical trials did not demonstrate the significance of lidocaine’s impact on mivacurium efficacy [22], this meta-analysis included only 2 studies evaluating this drug, and the p-value for lidocaine’s influence on various NMBAs was low (0.1). Therefore, the hypothesis of mivacurium and NMBA interaction cannot be categorically rejected. Due to the small sample size of our study, lack of measurement for one patient on the leg, and the atypical phenomena observed in several patients (such as no decrease in TOFratio to 0, TOFratio 0 throughout the measurement, and missing individual measurements due to signal interference), we decided not to further narrow down the group and exclude patients who received lidocaine. Secondly, the group was heterogeneous in terms of BMI, but the subgroup sample sizes were too small to perform a separate analysis of patients with normal weight, overweight, and obesity, although it is known that obesity interferes with the reliability of such measurements. Thirdly, in situations of missing data for individual measurements, we assumed the last available measurement for analysis, which could result in a possible shortening of time by 5 minutes, i.e., the interval of readings after exceeding 600 s. Setting more frequent reading intervals could significantly alter the results, especially in those patients where both the onset of blockade and the recovery occurred very quickly. Fourthly, our patients were from a Central European population with low ethnic diversity. Mivacurium is metabolized by butyrylcholinesterase [23]; although the activity of this enzyme depends on kidney and liver function, this drug is mainly eliminated in the serum, not in the kidneys or liver [24]. In our group, 5 patients received 1 mg of neostigmine + 0.5 mg of atropine to reverse neuromuscular blockade. Since enzyme function efficiency also depends on polymorphisms, whose frequency varies in different populations, the results of such studies should be cautiously extrapolated to genetically distant populations because the impact of polymorphisms on mivacurium metabolism is poorly understood [25,26]. Few publications indicate that this is not a very significant factor in the case of the Black race [27], but it is unknown how this issue affects other ethnic groups. Another limitation is that the difference in measurement values between the leg and the arm may be caused not so much by measurement error as by pathological factors. For example, it is known that a difference in SBP values between the lower and upper extremities of around 10 mmHg, as observed in this study, is an independent predictor of diabetes [28] and peripheral artery disease [29]. Therefore, it seems reasonable to deepen the research with a more precise clinical characterization of the evaluated population. Finally, the very idea of assessing TOFratio is sometimes questioned as overestimating recovery, and it cannot be ruled out that the use of modified TOFratio, as suggested by Schmartz et al, would yield different results [30].
The limitations of the monitoring methods themselves should also not be forgotten. In some cases, measurement is not possible due to interference [31]. Technical artifacts in electromyography monitoring include motion of the monitoring cable, transducer noise from electrode displacement, high skin-electrode impedance, intrinsic noise in the electromyograph monitor, and interference from nearby biomedical devices like pacemakers [32]. Such distortions are likely to produce distorted results. The risk of interference can be reduced by applying water, ECG cream, or ECG gel [31]. Unfortunately, we did not use such methods in our study because it ended before the publication that showed this.
On the other hand, the advantage of our study is that we were the only authors to evaluate the difference after mivacurium administration, and we are among the few researchers to assess arterial pressure and time to recovery.
Conclusions
Time-to-onset and SBP are comparable between these 2 methods, in contrast to time-to-recovery and DBP. This should be considered in case of the inability to apply the TOF-Cuff on the leg.
Figures
Figure 1. Kaplan-Meyer curve presenting time to onset of neuromuscular blockade after the first dose of mivacurium. Figure 2. (A) Bland-Altmann plot for the time to onset of neuromuscular blockade (train-of-four ratio=0) after the first dose of mivacurium. (B) Bland-Altmann plot for the time to recovery (train-of-four ratio >90) after the last dose of mivacurium. Figure 3. (A–D) Bland-Altman plot for values of systolic and diastolic blood pressure measured on the arms and on lower legs at the starting point and during neuromuscular blockade. Figure 4. Distribution of Spearman R correlation coefficient between series of measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in particular patients. Measurements were performed with TOF-Cuff on the legs and Drager Infinity Delta XL on the forearm of the hand where TOF-Scan was placed on the finger. TOF – train-of-four.Tables
Table 1. The number, percentage, and cumulative percentage of patients achieving specified ranges of the quotient of time to TOFratio=0 measured by TOF-Scan against the same time measured by TOF-Cuff. Table 2. The number, percentage, and cumulative percentage of patients achieving specified ranges of the quotient of time from the last mivacurium dose to TOFratio>90 measured by TOF-Scan against the same time measured by TOF-Cuff.References
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