Abstract
Objective:
Residual neuromuscular blockade (RNMB), defined as a train-of-four ratio (TOFR) <0.90, is a complication of neuromuscular blocking agents (NMBA). Data about RNMB in children are rare. This single-center observational trial evaluated the rate of neuromuscular monitoring (NMM), the incidence, and consequences of RNMB in pediatrics.
Methods:
Children over 1 month undergoing elective and urgent surgery during core work hours receiving NMBA were included in an 84-day observation period. When the anesthesiologist decided to extubate, a blinded investigator measured the TOFR by acceleromyography. Data on demographics, surgery, anesthesia, and outcome were recorded. Comparison of qualitative variables was done using the chi-square test. The Mann–Whitney U test was used to compare quantitative variables between patients with or without TOFR <0.90. P <0.05 was considered significant.
Results:
Eighty-nine children were included in the analysis. Rate of quantitative and qualitative NMM was 65.2% and 5.6%, respectively. Incidence of RNMB was 10.1% with TOFRs between 0.78 and 0.89 in 8 children and a TOFR of 0.48 in one child. Median time from the last NMBA administration to the TOFR before extubation was significantly shorter in patients with a TOFR <0.90 in comparison with a TOFR ≥0.90 (88 vs. 110 min). In the RNMB group, qualitative NMM was significantly more often used compared with the no RNMB group (22.2% vs. 3.8%). Adverse events were rare with no significant differences between the two groups.
Conclusion:
RNMB in children is a relevant hazard. Qualitative NMM is not reliable to exclude RNMB. Institutional training programs on neuromuscular management in children may be helpful to improve the rate of quantitative NMM.
Keywords: Neuromuscular monitoring, residual neuromuscular blockade, pediatric patients, postoperative pulmonary complications
Introduction
Neuromuscular blocking agents (NMBA) are frequently used in pediatric anesthesia.[1] Residual neuromuscular blockade (RNMB) after extubation, increases the risk of postoperative pulmonary complications (POPC).[2] In pediatrics, there are rare data about the incidence of RNMB, which ranges anywhere from 10% to 48%.[3,4,5] Spontaneous recovery of neuromuscular relaxation is unpredictable and has about 25% variance.[6] Clinical estimation of NMB and qualitative neuromuscular monitoring (NMM) are not able to exclude RNMB.[2,7] Application of sugammadex without NMM cannot protect from RNMB in adults and children.[8,9] Only the achievement of a train-of-four-ratio (TOFR) ≥ 0.90 measured by quantitative NMM indicates sufficient recovery from NMB.[10] Quantitative NMM and adequate dosing of reversal agents in accordance to recently published guidelines can decrease the rate of RNMB and the incidence of POPC.[7,10] At the anesthesiology department of the study hospital, an education program, including use of NMM and guideline conform reversal, was implemented before this trial was started. Every workplace was equipped with an acceleromyographic monitoring device via a Phillips IntelliVue NMT Module (Phillips Healthcare, Amsterdam, the Netherlands). For infants, the TOF-Watch® device (MIPM, Mammendorf, Germany) was available because of their lighter cables. In accordance with the standard operating procedure, every anesthesiologist was encouraged to routinely use quantitative NMM. Dosing cards for reversal agents were available at every workplace. The aim of this prospective, observational study was to estimate the rate of NMM, the incidence, severity, and the consequences of RNMB in pediatric patients under anesthesia at a German University Medical Centre.
Methods
After approval by the Institutional Ethics Committee (University of Regensburg, Germany (protocol N°17-449-101) and registration at www.ClinicalTrials.gov (NCT03804346), this single-center, prospective, observational study was performed between May 1, 2017, and July 23, 2017. Written informed consent was waived since this investigation was classified as quality-of-care examination due to its purely observational character. The anesthesiologists (attending physicians, fellows, and residents) responsible for anesthesia were aware of the objective of the investigation.
All children undergoing elective and urgent (operation within 6 hours after diagnosis) surgery during core work hours (8:00 a.m. until 5:00 p.m.) receiving NMBA were included in this study. Exclusion criteria were emergency procedures (immediately or within 1 hour after diagnosis), infants younger than 1 month, and children who were not planned to be extubated after the surgical procedure.
Study design and data collection
Recorded data included basic demographic information, preexisting medical conditions, preoperative medication, data related to surgery (type and timing), and anesthesia including professional experience of the anesthesiologist. Further data included adverse events during transfer to and in the postoperative care unit (PACU).
Neuromuscular monitoring
All decisions regarding anesthesia (including dosing of NMBA and reversal medication) were made by the responsible anesthesiologist based on criteria according to his/her standard practice without any interference of the investigator. At the end of surgery, when the anesthesiologist in charge decided to extubate the child, an independent investigator, blinded to the grade of relaxation, measured, and documented the level of neuromuscular blockade by acceleromyography (AMG). TOF count, TOFR and in case of deep NMB the post-tetanic count was measured at the adductor pollicis muscle stimulating the ulnar nerve. Measurement was performed in accordance with Good Clinical Research Practice guidelines without a hand adapter using non-calibrated acceleromyography (TOF-Watch SX® acceleromyograph, Organon Ltd., Dublin, Ireland).[11,12] Stimulation current was set at 50 mA (4 pulses of 0.2 ms duration at a frequency of 2 Hz).[11,13] Two consecutive stimulations were applied for each patient, separated by 15 s. If the result of the two measurements differed more than 10%, a third measurement was performed. The mean TOFR of the two closest measurements was used. If the mean TOFR was <0.90, the result was communicated to the responsible anesthesiologist to assure patient safety. If TOFR was ≥0.90 the responsible anesthesiologist was not informed. The decision to extubate or to reverse pharmacologically was left to the responsibility of the anesthesiologist in charge.
Detection of adverse events
Directly after tracheal extubation in the operation theatre, during transfer to PACU and during PACU stay adverse events (postoperative nausea and vomiting, severe pain, severe coughing, stridor/obstruction, broncho/laryngospasm, and oxygen desaturation) were recorded by investigators and nurses. Furthermore, we measured recovery of anesthesia by the Aldrete-Score in the PACU.
Statistical analysis
The observation period was not determined by a sample size calculation, but simply by a predetermined observation time of 84 days.
All data were analyzed using IBM SPSS Statistics Version 23 (IBM; Armonk, NY; USA). Comparison of qualitative variables was done using the chi-square test. The Mann–Whitney U test was used to compare quantitative variables between patients with or without TOFR <0.90. P <0.05 was considered significant. Qualitative variables were described as number (n) and percentage (%), while quantitative variables were expressed by median, first (Q1) and third quartile (Q3), minimum (min) and maximum (max) values.
Results
Patients
During the 84-day observation period, in total, 423 children were anesthetized. Of the 189 children who were endotracheally intubated, 175 received NMBAs for intubation. 10 children were transferred to the ICU endotracheally intubated. 61 patients were excluded for organizational reasons, such as overlapping with other recruited patients or premature extubation without NMM by the investigator. 104 children were primarily examined. In 15 children measurement was not possible because of technical difficulties of the TOF-Watch SX. In 8 cases, the uncalibrated AMG just displayed TOF-counts instead of TOFR.
In total, 89 children were included, and their data analyzed [Figure 1].
Figure 1.
CONSORT Flow Diagram. Patients were not measured if intubation was performed without NMBA, if the patients were transferred to the ICU endotracheally intubated and because of organizational reasons. Patients, who were measured, were excluded if neuromuscular measurement did not work because of technical difficulties of the TOF-Watch SX
Neuromuscular monitoring
In 63 children, NMM was used (70.8%), 58 (65.2%) were monitored quantitatively by AMG, 5 (5.6%) qualitatively by tactile assessment of the TOF stimulation. In 26 (29.2%) children, no NMM was used.
Incidence of RNMB
Incidence of RNMB (TOFR <0.90) was 10.1% (9 children) out of 89 patients which were included in the analysis. TOFRs were between 0.78 and 0.89 in 8 children. Severe RNMB (TOFR = 0.48) was found in one child (age: 7 months). In the no-RNMB group (80 children, 89.9%), TOFR was between 0.91 and 1.36. 33 children (37%) had a TOFR between 0.90 and 1.00. 47 children (52.9%) had a TOFR higher than 1.00. Demographics of the patients with a TOFR ≥0.90 and a TOFR <0.90 are presented in Tables 1 and 2. Distribution of different operative procedures is presented in Table 3.
Table 1.
Patient characteristics
| TOFR <0.90 | TOFR ≥0.90 | |
|---|---|---|
| Number of patients | 9 (10.1%) | 80 (89.9%) |
| Sex (male/female) | 4 (44%)/5 (56%) | 49 (61%)/31 (39%) |
| Age (years) Median (Q1-Q3) | 6 (1.50-8.00) | 5 (3.00-11.75) |
| Minimum - maximum | 0 (7 months) - 11 | 0 (4 months) - 17 |
| Weight (kg) Median (Q1-Q3) | 19.0 (11.9-35.0) | 18.5 (12.9-36.9) |
| Minimum-maximum | 6.9-47.0 | 7.0-90.0 |
| ASA physical status 1/2/3 | 5/2/2 | 43/26/11 |
ASA: American Society of Anesthesiologists
Table 2.
Distribution of age and TOFR in patients with residual paralysis
| Patient-ID | TOFR | Age (years) |
|---|---|---|
| 003 | 0.83 | 6 |
| 011 | 0.83 | 7 |
| 021 | 0.78 | 7 |
| 030 | 0.48 | 0 (7 months) |
| 047 | 0.87 | 11 |
| 063 | 0.89 | 2 |
| 065 | 0.88 | 1 |
| 083 | 0.87 | 9 |
| 097 | 0.87 | 3 |
Table 3.
Different operative procedures
| TOFR <0.90 | TOFR ≥0.90 | |
|---|---|---|
| Number of patients | 9 (10.1%) | 80 (89.9%) |
| Urgency (elective/urgent) | 9 (100%)/0 | 76 (95%)/4 (5%) |
| ENT | 7 (78%) | 41 (51%) |
| OMS | 0 (0%) | 12 (15%) |
| Neurosurgery | 0 (0%) | 5 (6.3%) |
| Traumatology | 0 (0%) | 1 (1.3%) |
| General surgery | 2 (22%) | 21 (26.4%) |
Number of patients (% of the cohort). ENT: ear, nose, throat medicine; OMS: oral and maxillofacial surgery
Children with RNMB had a significant shorter surgery (31 vs. 56 mins) and anesthesia duration (100 vs. 127 min) in comparison with no-RNMB. Almost exclusively rocuronium was used as NMBA. Only one child was paralyzed with succinylcholine in the no-RNMB group. The median time from the last NMBA administration to the TOFR before tracheal extubation was significant shorter in patients with TOFR <0.90 in comparison with a TOFR ≥0.90 (88 vs. 110 min) [Table 4]. Total amount of applied rocuronium was not different between the two groups, whereby in three patients rocuronium was redosed and in two children of the no-RNMB group reversal medication (neostigmine 0.05 mg kg-1, atropine 0.02 mg kg-1) was administered [Table 4]. In the RNMB group 8 anesthesiologists did not change their decision to extubate based on the investigator measured TOFR of <0,9 and no reversal agent was administered in these patients. In the child with severe RNMB the responsible anesthesiologist decided on spontaneous neuromuscular recovery monitored by the routine NMM and extubated at a TOFR of 0.95.
Table 4.
Timing parameters and NMBA application
| TOFR <0.90 | TOFR ≥0.90 | P | |
|---|---|---|---|
| Number of patients | 9 (10.1%) | 80 (89.9%) | |
| Surgery duration (min) | 0.035 | ||
| Median (Q1-Q3) | 31 (26.5-55) | 56 (36-96.5) | |
| Minimum - maximum | 13–107 | 7–374 | |
| Anesthesia duration (min) | 0.032 | ||
| Median (Q1-Q3) | 100 (81.5-109.5) | 127 (96-185.5) | |
| Minimum - maximum | 68-147 | 50–500 | |
| Rocuronium | 9 (100%) | 79 (98.7%) | 0.736 |
| Succinylcholine | 0 (0%) | 1 (1.3%) | 0.736 |
| Time from the last rocuronium application to extubation (min) | 0.048 | ||
| Median (Q1-Q3) | 88 (73-95.5) | 110 (83-167) | |
| Minimum - maximum | 68–142 | 46–493 | |
| Total rocuronium dose (mg/kg-1) | 0.720 | ||
| Median (Q1-Q3) | 0.34 (0.26-0.47) | 0.33 (0.27-0.41) | |
| Minimum - maximum | 0.20–0.55 | 0.11–0.78 | |
| Rocuronium redosing | 0 (0%) | 3 (3.8%) | 0.555 |
| Reversing Neostigmine + Atropine | 0 (0%) | 2 (2.5%) | 0.631 |
In children with RNMB, qualitative NMM was used significantly more often in comparison to those with a TOFR ≥0.90 (22.2% vs. 3.8%) [Table 5]. In 3 (33.3%) children in the RNMB group and in 23 (28.7%) children in the no-RNMB group, no NMM was used. Quantitative NMM was used selectively at the end of anesthesia in 4 (44.4%) children of the RNMB group and in 25 (31.3%) of the no RNMB group. Continuous quantitative NMM during the surgical procedure was not used at all in the RNMB group and only in 4 children (5%) of the no-RNMB group [Table 4].
Table 5.
Neuromuscular monitoring
| TOFR <0.90 | TOFR ≥0.90 | P | |
|---|---|---|---|
| Number of patients | 9 (10.1%) | 80 (89.9%) | |
| Use of NMM (qualitative + quantitative) | 6 (66.7%) | 57 (71.3%) | 0.774 |
| Qualitative NMM | 2 (22.2%) | 3 (3.8%) | 0.023 |
| Quantitative NMM | 4 (44.4%) | 54 (67.5%) | 0.169 |
| No NMM | 3 (33.3%) | 23 (28.7%) | 0.774 |
| Continuous, frequent use of quantitative NMM during procedure | 0 (0%) | 4 (5%) | 0.492 |
| Use of quantitative NMM only at the end of the procedure | 4 (44.4%) | 25 (31.3%) | 0.898 |
| Number of quantitative measurements | 0.356 | ||
| Mean±SD | 1.89±2.98 | 2.66±4.07 | |
| Median (Q1-Q3) | 2 (0-3) | 2 (0-3) | |
| Minimum–maximum | 0-9 | 0-30 |
Professional experience of the anesthesiologists
Anesthesiologists with professional experience of five to eight years used NMM in 64.1%, whereas lesser or more experienced anesthesiologists used NMM in 75.0% or 78.6%, respectively. The difference was not statistically significant.
Adverse events
There were no significant differences in adverse events between the RNMB and the no-RNMB group after extubation, during transfer to and stay in the PACU [Table 6]. We found no significant difference between the two groups regarding the Aldrete-Score at PACU arrival and discharge.
Table 6.
Adverse events postextubation, during transfer to the PACU and during stay at the PACU
| TOFR <0.90 | TOFR ≥0.90 | P | |
|---|---|---|---|
| Number of patients | 9 (10.1%) | 80 (89.9%) | |
| Postextubation | |||
| Median SpO2 (%) (Q1-Q3) | 96 (94.5-99) | 97 (95-99) | 0.849 |
| Minimum - maximum | 94–100 | 82–100 | |
| Application of Oxygen | 2 (22.2%) | 10 (12.5%) | 0.428 |
| Upper airway collapsibility | 0 (0%) | 4 (5%) | 0.492 |
| Suspicion of aspiration | 2 (22.2%) | 5 (6.3%) | 0.091 |
| Stridor | 0 (0%) | 3 (3.%) | 0.736 |
| Broncho/laryngospasm | 0 (0%) | 2 (2.5%) | 0.631 |
| Transport to the PACU | |||
| Median Lowest SpO2 (%) (Q1-Q3) | 91 (90.5-94.5) | 94 (91-96) | 0.234 |
| Application of Oxygen | 1 (11.1%) | 10 (12.5%) | 0.904 |
| SpO2 partially ≤94% | 7 (77.8%) | 46 (57.5%) | 0.256 |
| PACU | |||
| Aldrete-Score | |||
| Arrival (means±SD) | 8.6±1.3 | 8.6±1.2 | 0.932 |
| Median (Q1-Q3) | 9 (7-10) | 9 (8-9) | |
| Minimum-maximum | 7-10 | 5-10 | |
| Discharge (means±SD) | 9.3±1.1 | 9.4±0.7 | 0.631 |
| Median (Q1-Q3) | 10 (8.5-10) | 9 (9-10) | |
| Minimum-maximum | 7-10 | 7-10 | |
| Nausea & vomiting | 0 (0%) | 2 (2.5%) | 0.631 |
Discussion
This prospective, observational trial revealed that RNMB is still a frequently encountered problem in pediatric anesthesia. Shorter duration between last NMBA application and extubation is a risk factor for RNMB. Qualitative NMM is unreliable in assessing RNMB. Use of quantitative NMM was only observed in 65.2% of the included patients. Not using quantitative NMM increases the risk for RNMB.
Residual paralysis at the end of a surgical procedure is a relevant concern to anesthesiologists.[2] In contrast to adults, children present an age-dependent faster spontaneous and pharmacologically reversed recovery of neuromuscular function after the application of NMBA.[14,15] Incidence of RNMB (10.1%) in our trial was comparable to former studies, which revealed rates of RNMB between 10% to 48.2% for pediatric cohorts.[3,4,5] There is sufficient data about the consequences of RNMB in adults such as hypoxemia, reduced hypoxic ventilatory drive, difficulty breathing and swallowing, impaired pharyngeal function, hypercapnia, aspiration with consecutive pneumonia, impaired clinical recovery, and increased morbidity and mortality.[2] A large prospective, observational study in adults with no or minor risk factors for pulmonary complications showed an increased risk for POPC from NMBA, whereas NMM and pharmacological reversal did not reduce the risk for POPC.[16] Like Ledowski et al, we found low rates of adverse events (oxygen desaturation, upper airway collapsibility, stridor, and broncho/laryngospasm) after tracheal extubation, which were not significantly different between TOFR ≥0.90 and <0.90.[3] This contrasts with other findings showing that the application of NMBA increases the incidence of laryngo-/bronchospasm, of prolonged coughing and of oxygen desaturation after tracheal extubation 2 to 2.5 times.[17] Moreover, it doubles the rate of oxygen desaturation in the PACU.[17] In pediatrics, high doses of NMBA are associated with POPC. Especially infants, short duration surgical procedures and higher ASA risk scores predispose to respiratory side effects of NMBA.[18]
In accordance to Klucka et al.,[4] we found that a longer time interval between the last application of NMBA and tracheal extubation reduces the incidence of residual paralysis. In contrast to other investigators, almost exclusively rocuronium was used in our trial. However, even mivacurium caused rates of RNMB as high as 28%.[4] In addition, reversal rate of 2.5% in the no RNMB group with neostigmine and atropine was vanishingly low. Other studies showed pharmacological reversal rates of 41% to 80% using neostigmine and sugammadex in children.[3,4,5]
Only quantitative NMM at the adductor pollicis muscle can reliably identify residual paralysis.[10] Despite a recent educational program on this issue, standard operating procedures, dosing cards and easily available NMM devices, the rate of NMM in our trial was as low as 70.8% (65.2% quantitative and 5.6% qualitative NMM). In our trial, anesthesiologists used NMM more often than in other trials.[3] A recent Chinese questionnaire revealed, that 83% of the interviewed anesthesiologists never use neuromuscular monitoring in pediatric anesthesia, whereas 98% use neostigmine as reversal agent regularly.[19] Our study indicates in comparison to other trials that information about the harms of NMBA and necessity of NMM might improve compliance to recommendations. Nevertheless continuous, repetitive quantitative monitoring was only found in 5% of the no RNMB group. In the RNMB group no child was measured continuously.
Qualitative NMM, which is known to be unreliable to detect residual NMB, was used significantly more often in the RNMB group (22.2% vs. 3.8%).[7] One third of the patients (33.3% RNMB group, 28.7% no RNMB group) was not monitored at all. Anesthesiologists with a professional experience of 5-8 years had the lowest rate of NMM (64.1%) in comparison to residents and more experienced consultants. This conflicts existing evidence suggesting that clinical muscle function tests cannot reliably exclude RNMB, which was taught in the institutions educational program.[7] Although the 8 anesthesiologists (6 with experience of 5-8 years) were informed about a TOFR <0.90 by the investigator, none changed the decision to extubate or decided to reverse pharmacologically. In view of the training program this might be a sign of overconfidence in their ability to manage NMB intuitively without NMM.[20]
Limitations
This trial has several limitations. First, the responsible anesthesiologists were informed about this study. This may have created a bias to more NMM. Nonetheless just two out of three used quantitative NMM.
Secondly, we excluded infants younger than 1 month, emergency cases and anesthesiological procedures outside regular working hours. Despite an observation period of almost three months the number of included children, might have been too low (n = 89) to achieve a statistical significance regarding adverse respiratory events between RNMB and no-RNMB group.
Third, we used the AMG measurement immediately prior to tracheal extubation, which reflects the situation after extubation indirectly. We chose this strategy of NMM, because using stimulation currents of 50 mA might be painful and not appropriate in awake children. A stimulation current of 50 mA was a compromise between accuracy, precision, and discomfort.[13,21] This setting, which was used by a couple of prior studies partly in awake patients, did not allow calibration of the TOF-Watch SX.[3,4]
Fourth, it is a known phenomenon that AMG overestimates recovery of NMB partly by at least 0.15 in comparison with electromyography, the reference technique.[22] For that reason, some authors already claimed a new threshold of TOF ratios ≥1.0 to exclude residual NMB with AMG.[23]
Fifth, the observation period of the patients ended after discharge from the PACU. POPC occurring days after anesthesia were not detected.
Conclusion
RNMB in children is a frequent, underestimated hazard for potential respiratory adverse events. Qualitative NMM is not reliable to exclude residual paralysis in children. Education and training programs may be helpful to increase the frequency of quantitative NMM. The low rate of continuous, quantitative NMM demonstrates the need for better education to increase awareness of RNMB. International guidelines on monitoring and antagonism of neuromuscular blockade in children are desirable to reduce RNMB. Further large clinical trials are needed to explore the consequences of RNMB in children.
Ethics Committee
University of Regensburg, Germany: protocol N°17-449-101.
Main Points
A single-center observational trial identified postoperative residual neuromuscular blockade as a common problem in pediatric anesthesia using neuromuscular blocking agents. Qualitative neuromuscular monitoring is unreliable to identify residual neuromuscular blockade in pediatrics. The omission of quantitative neuromuscular monitoring increases the risk of residual muscle relaxation.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
References
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