In adult and paediatric patients, neuromuscular blocking agents (NMBAs) are widely used in clinical anaesthesia and emergency medicine to facilitate tracheal intubation,1 mechanical ventilation and to allow surgical access to body cavities.2 The use of NMBA is associated with the risk of residual neuromuscular blockade (RNMB).3 The use of NMBAs has been associated with an increased risk of respiratory adverse events in children undergoing anaesthesia, particularly in the early postoperative period.4 Furthermore, due to limited predictability in individual patients2 and differences in body composition during growth,5 neuromuscular management is particularly challenging in paediatric patients. Neuromuscular monitoring is an evidence-based practice in adult patients and should be used routinely when NMBAs are used. Moreover, objective neuromuscular monitoring can prevent RNMB and related morbidity and mortality by ensuring that the TOF ratio has recovered to 0.9 before extubation.6–8
Good clinical research practice (GCRP) guidelines on pharmacodynamic studies of NMBAs recommend that the neuromuscular monitor must present a stable response (baseline – less than 5% variation at T1 height) for a period of 2 to 5 min before administration of an NMBA.9 The time required to reach this stable response may vary, but may be shortened by applying tetanic stimulation for 5 s. Tetanic stimulation to decrease the time required to reach a stable response is well documented in adults10,11 but not in paediatric patients. Therefore, we designed a study in which the effect of tetanic stimulation on neuromuscular monitoring in paediatric patients was investigated. The primary objective of this study was to evaluate whether tetanic stimulation affected parameters of onset of, and recovery from, a single dose of rocuronium 0.6 mg kg−1 in children.
The secondary objectives included assessment of the initial and final T1 height, time to obtain initial T1 height stability and monitor settings (electric current and sensitivity).
Materials and methods
This single-centre, open-label, randomised controlled trail was performed at Child Institute of Clinics Hospital of São Paulo University Medical School between January 2014 and July 2015. Ethical approval for this study (protocol number: 11.398/2013) was provided by the Ethical Committee of Clinics Hospital of São Paulo University Medical School, São Paulo, Brazil (Chairperson Prof A. J. Mansur) and registered with ClinicalTrials.gov (NCT02498678).
After obtaining written informed consent from the parents of the patients, 50 patients [American Society of Anesthesiologists (ASA) physical status I to II, aged 2 to 11 years] scheduled for abdominal and/or perineal surgery (estimated surgical time greater than 60 min) were included in the study. Exclusion criteria included patients with diseases or on medications known to interfere with neuromuscular transmission, hepatic or renal dysfunction, and allergy to medications used in the study.
Randomisation was by computer-generated random number allocation stored in sealed, opaque envelopes. The seal of the envelope was broken by trained study personnel after the induction of general anaesthesia.
For patients in the control group (C), train-of-four (TOF) stimulation was commenced and continued every 15 s. After 1 min of stimulation, calibration and supramaximal stimulation was performed using the built-in calibration function (CAL 2) of the TOF-Watch SX device (Organon Ireland Ltd., a subsidiary of Merck & Co., Inc., Swords, Co., Dublin, Ireland). When the variation at T1 was greater than 5%, subsequent calibrations were applied until a stable signal was received. For patients in the tetanic stimulation group (T), a 50-Hz tetanic stimulation was applied for 5 s and followed by 1 min of TOF stimulation every 15 s. This was followed by calibration and supramaximal stimulation using the built-in calibration function (CAL 2) of the TOF-Watch SX device.
Patients were monitored using electrocardiography, noninvasive blood pressure measurements, pulse oximetry, capnography, a gas analyser and bispectral index (Draeger Medical Systems, Telford, Pennsylvania, USA). Anaesthesia was induced either with inhaled sevoflurane or intravenous anaesthesia (propofol, 2 to 4 mg kg−1 and sufentanil, 0.3 to 0.5 μg kg−1) according to the patient's ability to cooperate while obtaining venous access. Anaesthesia maintenance was with a continuous infusion of propofol and additional doses of sufentanil as needed. Peripheral temperature was measured at the thenar eminence of the upper limb and maintained above 32°C. Core temperature was monitored in the oesophagus and maintained above 35°C. All patients were placed under an upper body forced air warming blanket (Bair Hugger; Arizant Healthcare Inc., Eden Prairie, Minnesota, USA).
After the induction of anaesthesia, the trachea was intubated without the use of NMBA. Mechanical ventilation was adjusted to maintain normocapnia (end-tidal CO2, 32 to 40 mmHg). Before commencing the study procedures, the absence of inhaled sevoflurane was confirmed by gas analysis monitoring. The intravenous line for the rocuronium administration was inserted in the contralateral arm. The choice between the dominant and nondominant arm was made randomly. After the calibrating procedures were performed, rocuronium 0.6 mg kg−1 was administered in a fast-running physiological saline infusion within 5 s. The recovery of neuromuscular blockade (NMB) was spontaneous.
Neuromuscular monitoring procedure
Neuromuscular monitoring was performed using the TOF-Watch SX, by measuring the effect of stimulation of the ulnar nerve on activity of the adductor pollicis muscle. The electrodes were positioned near the wrist and the ulnar nerve. The acceleromyographic transducer was firmly placed on the ventral aspect of the top of the thumb, perpendicular to the movement of the thumb. The specific procedures for both groups (C and T) were described in the study design section. The acceleromyographic data were collected and stored on a laptop using the TOF-Watch SX monitor computer program (version 2.5.INT; Organon Ltd., Dublin, Ireland). Neuromuscular monitoring was performed according to the recommendations of GCRP in pharmacodynamic studies of NMBAs.9
Neuromuscular monitoring parameters
The following parameters were monitored and compared for both (C and T) groups: time to initial T1 height stability (time required to obtain the stability of T1 height before NMBA administration), initial T1 height (T1 height before NMBA administration), the onset time of the NMB (time to 95% T1 height depression), time to the reappearance of T1, T2, T3 and T4; time to the uncorrected (not normalised) and normalised TOF ratios reaching the following levels: 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80 and 0.90; time to T1 recovery reaching 25 and 75% of final T1 value, that is duration 25 and 75%, respectively. The recovery interval from 25 to 75% (elapsed time between T1 25% and T1 75%) and the final T1 height (T1 height after recovery of neuromuscular function) were also recorded. Furthermore, the monitor settings (sensitivity and electric current) were collected.
Normalisation of recovery parameters
During recovery, the twitch height does not always return to the control value. Therefore, all recovery parameters based on the twitch height (i.e. duration 25%) should be adjusted to the final T1 value (normalisation). If, for instance, the final T1 is 80%, a recorded T1 value of 20% should be adjusted to 25% (0.20/0.80).
The sample size of this study was based on the results of a study by Bock et al.,10 in which the time to reach a TOF ratio of 0.9 in paediatric patients after a single intubating dose of 2 x ED95 rocuronium was 42.8 (±9) min. We postulated that by using tetanic stimulation prior to TOF monitoring, the average time to reach a TOF ratio of 0.9 would not be less than 35 min. With 80% power and 95% confidence, the sample size required to conduct the study was 21 patients in each group.
Statistical analysis was performed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, Washington, USA) and IBM SPSS Statistics version 20 (IBM Corporation, Armonk, New York, USA). The Student's t test was used for normally distributed continuous variables. The Mann–Whitney U test was used for nonnormally distributed continuous variables. The Chi-square test was used for categorical variables. Data are presented as mean ± standard deviation (SD). P values less than 0.05 were considered statistically significant.
Fifty patients were enrolled in this clinical trial. Two patients in the T group were excluded from data analysis as a result of interference from the surgical team during data collection (Fig. 1). Results from 48 patients were therefore included in the analysis (Table 1). Patients were followed throughout their hospital stay. No complications related to neuromuscular monitoring were reported postoperatively. Crossover to the other group did not occur.
Neuromuscular monitoring characteristics are summarised in Tables 2 and 3. There was no significant difference in mean onset time [C: 57.5 (±16.9) vs. T: 58.3 (±31.2) s; P = 0.917]. Mean times to normalised TOF ratios of 0.7, 0.8 and 0.9 were significantly shorter in the tetanic stimulation group [C: 40.1 (±7.9) vs. T: 34.8 (±10.0) min; P = 0.047, C: 43.8 (±9.4) vs. T: 37.4 (±11.0) min; P = 0.045 and C: 49.9 (±12.2) vs. T: 41.7 (±13.1) min; P = 0.026, respectively]. The mean time required for T1 height stabilisation was similar in the two groups [C: 195.0 (± 203.0) vs. T: 116.0 (±81.6) s; P = 0.093], but the initial and final T1 height values were significantly lower in the tetanic stimulation group (C: 98.0 vs. T: 82.7%; P < 0.001 and C: 95.3 vs. T: 69.3%; P < 0.001, respectively).
In this randomised, open-label, controlled trial, we compared the onset and recovery parameters after a single bolus dose of rocuronium in children as measured by a neuromuscular monitoring device calibrated with or without tetanic stimulation. Our results suggest that the application of tetanic stimulation may shorten recovery times. Furthermore, the calibration of the monitor in the tetanic stimulation group had limitations to setting T1 height to 100%.
Lee et al.11 studied three groups of adult patients using mechanomyography under nitrous oxide–isoflurane anaesthesia. Different electrical stimuli schemes were applied to both ulnar nerves, enabling a paired analysis within each group. They found that either 2 or 5 s of tetanic stimulation preceding a 2-min stabilisation period resulted in clinical recovery values comparable to that from a 20-min stabilisation period. Moreover, the control arm receiving TOF stimuli for 20 min in all groups had a significant increase in T1 height that was not observed in groups receiving tetanic stimulation for 2 to 5 s.11
Kopman et al.12 used acceleromyography (TOF-Guard Organon, Boxtel, The Netherlands) to compare three groups of 10 adult patients each receiving three different electrical stimuli. They concluded that a 5 s 50 Hz tetanic stimulus administered before initial twitch calibration considerably shortened the time required to achieve baseline stability using the acceleromyography method. In addition, they found a great variation in T1 height at the end of the experiment in the TOF and 1 Hz groups [158 (±26) and 142 (±19), respectively]. In the tetanus group, T1 height ranged only between 97 and 105% of the controls. However, NMBAs were not used in this study.12 On the basis of these previous findings, the last international consensus for GCRP in pharmacodynamic studies of NMBAs advocated the application of tetanic stimulation at 50 Hz for 5 s immediately before calibration.9
However, the findings of our study of paediatric patients are in contrast with those recommendations. This could be because the monitor calibration in the tetanic stimulation group was performed just after the stimulus that coincides with the beginning of the period of posttetanic potentiation (PTP). Repetitive, indirect stimulation of skeletal muscle may cause potentiation of the evoked twitch tension, and this enhancement persists for a period of time before returning to the default response. Krarup13 showed that the increase in twitch tension after tetanic potentiation was 27 (±4)%, which returned to pretetanus values between 6 and 10 min after tetanus.
By using the default CAL 2 function, the TOF-Watch SX automatically determines the supramaximal current and simultaneously adjusts the T1 height to 100%. The T1 height adjustment is done through the sensitivity parameter (i.e. how the sensor measures muscular acceleration). It can be adjusted between 1 and 512, where 512 represents the most sensitive setting. The more intense the muscle contraction, the smaller the sensitivity value, and vice versa. A sensitivity setting of 157 is the default value.14
Our results showed that the mean sensitivity value in the tetanic stimulation group was lower than in the control group (Table 4 and Fig. 2). However, this difference was not statistically significant. This may be as a result of calibration, which occurs at a time of increased mechanical response. Accordingly, the monitor reduced its sensitivity during calibration to compensate for this increased mechanical response that occurs during PTP. In addition, this lower sensitivity could lead to a lower degree of differentiation between T1 and T4 responses (fading) during the NMB recovery phase. Hence, the final stages of the NMB would be reached sooner in the tetanic stimulation group, despite there being no statistically significant difference between the two groups. Kopman et al.12 also found significant differences in T1 heights just after the monitoring device was calibrated. Although the TOF and the 1 Hz group showed values of 101 ± 4 and 101.5 ± 4%, respectively, the tetanus group showed a value of only 90 ± 7.7% (range, 79 to 105%). The authors justified this lower value because twitch calibration occurred in the immediate posttetanic period. In light of these variations in ‘control’ twitch height, initial T1 values in all three groups were normalised to equal 100% at time 0 (the first recorded TOF response after calibration). Our data showed similar results regarding the initial T1 height between the control group and tetanic stimulation group (98.0 vs. 82.7%; P < 0.001, respectively). Although a function of the automatic calibration (CAL 2) is to adjust the T1 height to 100%, this was impossible in the tetanic stimulation group. Despite there being no statistically significant difference between the two groups, we think that the lower sensitivity values in the tetanic stimulation group may be the reason for the lower initial T1 height. This means less sensitivity to muscular acceleration that, in turn, precludes the T1 height adjustment to 100%. Similarly, the final T1 height values also showed a statistically significant difference between the groups (95.3 vs. 69.3%; P < 0.001, respectively). Despite the low mean value of final T1 height during the recovery phase in the tetanic stimulation group, it is in accordance with the recommendations of GCRP, in which a stable T1 response should be 80 to 120% of the control (baseline) value.9
In the present study, the use of tetanic stimulation was tested for shortening the time to reach T1 height stability. The time required for T1 height stabilisation showed no statistically significant difference between the two groups. The results of our study in paediatric patients are in contrast with those of Kopman et al.,12 which showed that a 5 s, 50 Hz tetanic stimulation before initial twitch calibration considerably shortens the time required to achieve baseline stability in adults patients.
As aforementioned, PTP is a transient phenomenon and therefore we suggest two possibilities to avoid this phenomenon interfering with neuromuscular monitoring: performing calibration immediately after tetanic stimulation (with possible manual height adjustment to 100%) or waiting a longer period before calibrating the monitoring device after application of the tetanic stimulus. We opted not to perform a manual T1 height adjustment to 100%, through manual sensitivity adjustment, as we believe that this procedure is cumbersome and limits its use in real time. In addition, the T1 height visualisation is possible only through the TOF-Watch SX monitor computer program. Hence, this is a procedure that has a place only in data analysis, after the end of data collection, which restricts its utility in clinical practice. We therefore suggest a longer waiting period between applying tetanic stimulation and calibration of the neuromuscular monitor device.
This study has some limitations. Preload increases the precision of acceleromyography,15 but there is no study on its use in paediatric patients. The appropriate preload force to be applied in paediatrics is still unknown and so we did not apply preload in our study. As our study included only children classified ASA I or II without NM transmission disorders and undergoing elective surgery, the results cannot be extrapolated to other populations. Our investigation also covered a wide paediatric age range. The body composition differs according to age, and increases in BMI during childhood are generally attributed to the lean rather than to the fat component of BMI.5 The impact of this proportionally greater lean body mass on neuromuscular monitoring is unknown.
In conclusion, tetanic stimulation shortened the mean times to normalised TOF ratios of 0.7, 0.8 and 0.9, but there was no difference in the mean onset time or the mean time required for T1 height stabilisation after a single dose of rocuronium 0.6 mg kg−1 followed by spontaneous recovery in children aged 2 to 11 years. More studies are needed in paediatric patients to confirm our results, to determine the usefulness of tetanic stimulation to shorten the time required for stabilisation and the safety concerning the shorter recovery times. We strongly believe that a longer waiting period should be considered between applying tetanic stimulation and calibration of the neuromuscular monitoring device in paediatric patients.
Acknowledgements relating to this article
Assistance with the study: this work was carried out at Child Institute, Hospital das Clínicas, São Paulo University Medical School, São Paulo, Brazil.
Financial support and sponsorship: this work was supported by Department of Anesthesiology, Child Institute, Hospital das Clínicas, São Paulo University Medical School, São Paulo, Brazil.
Conflicts of interest: none.
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