Introduction

Neuromuscular block agents facilitate intubating conditions in general anesthesia patients by immobilizing vocal cords [1, 17]. However, they are associated with significant residual postoperative paralysis and morbidity [3]. Complete clearance of the agent’s action is essential to safe recovery in the postanesthetic care unit, but it is sometimes incomplete even after using reversal agents [3, 8]. Therefore, postoperative complications remain commonly derived from residual neuromuscular blockade [3, 8]. Acceleromyography is the standard neuromuscular block monitoring in clinical practice; it relies on the train-of-four nerve stimulation pattern recommendation: or the ratio of the fourth twitch to the first twitch T4/T1 ratio [11]. A train-of-four ratio of 0.7–0.9 is associated with impaired airway protective reflexes, upper airway obstruction, and postoperative hypoxemia [6, 12]. Therefore, full recovery of neuromuscular function should be present at the time of tracheal extubations [12]. Recent research argues that specific devices using raw acceleromyography may overestimate neuromuscular recovery and that the train-of-four ratio must recover to 0.99 or even 1.00 to exclude residual paralysis in this setting [5, 12, 15]. Our study aims to investigate the rate of the underdiagnosed residual neuromuscular block based on these two train-of-four ratio criteria (< 0.91 and < 1.00) to provide a framework to improve patient safety during surgery. Additionally, using crosstables, we calculated the relative risk, absolute risk, and Odds ratios for patients over 65 as compared to patients under 65 on the risk of residual neuromuscular block.

Methods

We performed a retrospective observational cross-sectional study adhering to STROBE guidelines. The protocol was approved by the General Hospital of Mexico Ethics and Research Committee by the number: DI/20/101/03/77; informed consent was waived because of being a retrospective study. We reviewed the clinical files of patients undergoing Ear-Nose-Throat (ENT) surgery from June 2018 to December 2018 in the General Hospital of Mexico. Inclusion criteria were adult patients (over 18 years) with an American Society of Anesthesiologists score (ASA) risk between I and III, having TOFR monitoring throughout balanced general anesthesia (induction with intravenous fentanyl and propofol and anesthetic maintenance with inhalational sevoflurane) using neuromuscular block with rocuronium (ponderal dose 0.3–1.2 mg/kg) at a single dose. Exclusion criteria considered any muscle relaxant other than rocuronium, patients requiring additional muscle relaxant doses during surgery, muscle-related diseases or allergies, magnesium sulfate or antiepileptics medication, or illnesses affecting TOFR evaluation and incomplete medical records. We collected demographic and anthropometric data, ASA score, NMBA and dose, TOFR registers at 5 min, 30 min, 60 min, and end of the surgery, anesthesia time in minutes, surgery time, and administration of reversal agent. We performed descriptive statistics (frequencies and percentages) for demographic data; we used mean dispersion measures (mean, standard deviation, 95% CI) for continuous variables. We used graphics to demonstrate the curve of NMB during surgery and residual NMB as the outcome in percentages. We used cross tables for residual NMB using two criteria, including TOFR < 0.91 or TOFR < 1.00. We made a sub-analysis for residual NMB using both criteria on patients under and above 65 years old. Table 1 includes the dataset of the whole sample and variables studied for statistical analysis.

Table 1 Sample and variables dataset
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TOFR recording process and documentation

All TOFR Recordings performed were done using an acceleromyographic portable Drager TOFScan® locating two electrodes on the wrist and the distal forearm of the non-dominant hand to stimulate the first finger abductor and register its movement using the second or third finger as reference (Fig. 1), TOFR measure is performed initially just before starting neuromuscular block, then forward we performed secondary measures at 5, 30 and 60 minutes as well as at the ending of the surgical procedure, where we keep monitoring up until the patient reaches a TOFR of 1.00 or above (raw data) before proceeding to extubate the patient. Given the retrospective nature of the study, the administration of reversal agents was performed based on the treating anesthesiologist’s criteria. All anesthetic events and recordings are documented on the anesthesia sheet, and data extraction for this study was gathered from these patients’ files.

Fig. 1
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TOFR measurement and electrodes disposition

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Results

We included 57 patients and excluded no patients; 43 females (75.4%) and 14 males (24.6%). The mean age was 41.74 years old (16.62 standard deviation (SD), 95% confidence interval (CI) at 37.33–46.15), and the mean body mass index (BMI) was 26.56 kg/m2 (4.72 SD, 95%CI at 25.30–27.81 95%). Patients more frequently had an ASA score of II (36 patients, 63.2%), followed by I (13 patients, 22.8%), and lastly, III (8 patients, 14.0%). The mean anesthetic time was 139.42 min (59.92 SD, 95%CI at 123.52–155.32), while the mean surgical time was 116.14 min (55.69 SD, 95%CI at 101.36–130.92). All 57 patients received a rocuronium at a mean ponderal single-dose of 0.50 (0.10 SD, 95%CI at 0.47–0.49) mg/kg. Mean TOFR values were as follows: 5 min 0.029 (0.06 SD, 95%CI at 0.01–0.04), 30 min 0.19 (0.20 SD, 95%CI at 0.13–0.24), 60 min 0.67 (0.31 SD, 95%CI 0.59–0.76), and at the end of surgery (outcome) 0.97 (0.20 SD, 95%CI at 0.92–1.03). Figure 2 compares the mean TOFR values in patients below and over 65 years old over time. Figure 3 compares the percentage of NMB over time according to the different TOFR criterium, TOFR < 0.91 or TOFR < 1.00. Figure 4 compares the percentage of NMB in patients under and above 65 years old over time according to TOFR < 0.91. Figure 5 compares the curve of NMB in patients under and above 65 years old over time according to TOFR < 1.00. Figure 6 compares the rates of underdiagnosis, diagnosis, and overdiagnosis of residual NMB to recovered patients according to the different TOFR criterium, TOFR < 0.91 or TOFR < 1.00. The residual NMB in our series was 29.9 to 49.1%, depending on the criteria used (TOFR < 0.91 or TOFR < 1.00, respectively). By subgroup analysis, patients below 65 years old had residual NMB varying from 27.5 to 45.1%, while patients above 65 years old were in the range of 50.0 to 83.3% using the different TOFR criteria (< 0.91 and < 1.00, respectively). Patients under 65 years old had a minimum NMB effect of at least 60 minutes; with almost 74.51% (38/51 patients) of them exceeding 90 minutes; while none of the patients above 65 years old were below 90 minutes, with a minimum of 110 minutes. Using TOFR criteria of < 0.91, cross tables for residual NMB in patients above 65 years old demonstrated an increased Absolute Risk (AR) ratio of 0.22, Relative Risk (RR) ratio of 1.82, and Odds Ratio (OR) of 2.64 as compared to patients under 65 years old. Using TOFR criteria of < 1.00, cross tables for Residual NMB in patients above 65 years old demonstrate an increased Absolute Risk (AR) ratio of 0.38, Relative Risk (RR) ratio of 1.84, and Odds Ratio (OR) of 6.09 as compared to patients under 65 years old. Seven (12.3%) patients had clinical symptoms of residual neuromuscular block presented as swallowing weakness in the postanesthetic recovery room, having a final TOFR below 1.00 before leaving the surgical room, two of them had a TOFR below 0.91, and surprisingly one of them had a TOFR of 0.64. The sensibility of a TOFR < 0.91 to detect clinical signs of residual neuromuscular block was 43%, the specificity was 72%, the Positive Predictive Value (PPV) was 18%, and the Negative Predictive Value (NPV) was 90%, with an AR of 0.07, a RR of 1.76 and an OR of 1.93. The sensibility of a TOFR < 1.0 to detect clinical signs of residual neuromuscular block was 100%, the specificity was 58%, the PPV was 25%, and the NPV was 100% with an AR of 0.25, and non-determined RR and OR because of no false negative cases. The AR for patients over 65 with clinical symptoms of residual neuromuscular block was 0.42, with a RR of 6.37 and an OR of 11.75. None of the patients required to be re-intubated, nor did they have a respiratory compromise. None of the patients receiving sugammadex presented clinical symptoms of residual neuromuscular block. Four patients presented complications, two (3.5%) had upper respiratory tract infections, and the other two (3.5%) had lower respiratory tract infections during their in-hospital stay. One of the patients with a lower respiratory tract infection had a final TOFR of 0.64, while the other had a value of 0.95; none had any documented clinical signs of residual neuromuscular block. Among the patients with upper respiratory tract infections, one had a final TOFR value of 1.44, and the other had a TOFR value of 0.91 with swallowing weakness in the recovery room. The sensibility for a < 0.91 to predict a lower respiratory tract complication (infection) was 50%, with a specificity of 69%, with a PPV of 5% and an NPV of 97% with an AR of 0.03, a RR of 2.17 and an OR of 2.23. The sensibility for a < 1.0 to predict a lower respiratory tract complication (infection) was 100%, with a specificity of 53%, with a PPV of 0.07 and an NPV of 100%, with an AR 0.07, and unable to determine RR and OR (because of a 0 false negative cases). All lower respiratory tract infections occurred in patients under 65 years with an AR of 0.04 and RR and OR of 0 each.

Fig. 2
figure 2

Compares the mean TOFR values in patients below and over 65 years old over time

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Fig. 3
figure 3

Compares the percentage of NMB over time according to the different TOFR criteria, TOFR < 0.91 or TOFR < 1.00

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Fig. 4
figure 4

Compares the percentage of NMB in patients under and above 65 years old over time according to TOFR < 0.91

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Fig. 5
figure 5

Compares the curve of NMB in patients under and above 65 years old over time according to TOFR < 1.00

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Fig. 6
figure 6

Compares the rates of underdiagnosis, diagnosis, and overdiagnosis of residual NMB to recovered patients according to the different TOFR criterium, TOFR < 0.91 or TOFR < 1.00

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Discussion

Current standards for quality care in anesthesia were first reported approximately in 2010 to increase patient safety during general anesthesia [7]. Many medical associations, including the Czech and French Societies of Anesthesiology, The Association of Great Britain and Ireland, stated the mandatory need for objective monitoring of neuromuscular block. They recommended a TOFR cut-off value of 0.90 for detecting residual NMB [7]. It is to highlight that the American Society of Anesthesiologists made no mandatory recommendation [7] on the use of NMB monitoring; in Mexico, there neither exists specific guidelines in this respect; nevertheless, it is common practice among our institution. We are proud to have a high acceptance rate among our anesthesia personnel for objective NMB monitoring, provided that all our institutional anesthesia equipment has integrated TOFR and that our institution participates in the High Proficiency Residence Program in anesthesia. Nevertheless, we are well aware that such an acceptance rate is not common practice worldwide yet [16]. Other problems, such as the availability of reversal agents, also play a role in mid to low-income countries such as ours as a cause of suboptimal treatment, an issue we will handle deep below.

The use of NMBA has significantly impacted current clinical practice for patients, anesthesiologists, and surgeons in many ways, including improved first-pass intubation for experts in elective conditions and non-experts in emergency conditions, aid for difficultness in facemask ventilation, enhanced surgical conditions for open and laparoscopic intermuscular approaches such as those of abdominal and pelvic procedures [17] in such a way that today NMB is considered vital for uneventful rapid sequence intubation [17].

Despite almost 80 years of experience in using NMB, several studies continue to report high incidence rates of residual neuromuscular block with the accompanying side effects and risks that it provides. Residual neuromuscular block increases the risk of pulmonary aspiration events and the hypoxic ventilatory response [14]. Respiratory complication rates reach 0.8% up to 6.5 of patients undergoing general anesthesia, which translates to 0.5 million up to 4 million worldwide yearly [3, 7]. Furthermore, the use of NMBDs has been repeatedly implicated in awareness during surgery when paralyzed patients have an inadequate level of anesthesia; such findings suggest that many clinicians may have an incomplete understanding of the pharmacology of NMBDs and of the existing techniques to monitor the level of the neuromuscular blockade after NMBD administration [14].

Mechanomyography (MMG) is the gold standard for monitoring neuromuscular function. Nevertheless, acceleromyography (AMG) is increasingly being used in a clinical setting as it is relatively inexpensive, easy to set up, and able to detect neuromuscular blocks with accuracy [15]. However, the baseline TOFR measured using AMG is significantly higher than MMG [15]. Authors used acceleromyograph (AMG) TOFR data, AMG- measured TOFR can exceed over 100. Raw AMG data have an idiosyncrasy. In contrast to MMG and electromyography (EMG) where the control (baseline) TOFR approximates 1.00 (100%), the control AMG-measured TOFR is more likely to be > 1.00 (> 100%). Values between 1.10 (110%) and 1.20 (120%) are common, and values of 1.40 (140%) are not rare [13, 15]. The current standard for “adequate recovery” from a neuromuscular block is the return of the TOFR to ≥0.9 measured at the adductor pollicis muscle, the cut-off point when an extubating is considered safe. Nevertheless, recent studies have suggested that several devices offer clinical raw TOFR data which can report values over 1 (or 100 in percentage) that require additional baseline calibration and suggest corrected values in the range of > 0.95–1, with trending to < 1.00 [4, 13, 15].

Additionally, to the possible incomplete understanding of the NMB effects and pharmacokinetics, a significant rate of underused monitoring is reported worldwide either by lack of devices, protocols, or culture to use monitoring [13, 16]. As considered above, this problem is complicated even more when there is difficulty acquiring trustable and sensible cut-off values [15]. Provided these issues, currently available devices are less than ideal, and expertise on their use is far from real [13].

Underdiagnosing RNMB is not surprising considering the lack of implementation and expertise on NMB monitoring and the variations in device parameters and cut-off criteria, which make unneeded reversal even plausible, as was the case in one of our cohort patients. Adding to the already high rate of RNMB poses a significant risk of complications, especially in high-risk populations such as older people and patients with serious comorbidities. Reversal agents significantly reduce this collateral damage; nevertheless, they are not without risk. Reversal agents can have serious detrimental effects in the postoperative period. Traditionally, we achieve the reversal of neuromuscular block by administering acetylcholinesterase inhibitors [14]. These drugs, such as neostigmine, have significant parasympathomimetic effects as acetylcholine interacts with cholinergic receptors [14]. For instance, these agents cause bradycardia and other bradyarrhythmias and bronchoconstriction through muscarinic receptor activation. In order to mitigate these effects, anti-muscarinic agents are co-administered with acetylcholinesterase inhibitors [14]. Once recovery is almost complete, administration of these agents may have the paradoxical effect of inducing muscle weakness [14]. Therefore untimely or wrong administration (as in the setting of an overestimated residual NMB) can produce instead of preventing serious pulmonary events.

Additionally, the type of reversal agent is also essential; there exists evidence that sugammadex reduces the risk of pulmonary complications by up to 30% [9]. Based on this information, we prefer using sugammadex at our institution, which is also in line with current US trends for NMB reversal during ENT surgery [2] . Sugammadex acts as a binding agent and has no effect on acetylcholinesterase [14]. Therefore, such reversal is devoid of the various side effects of acetylcholinesterase inhibition. Sugammadex, although safer, is not free from side effects, with hypersensitivity reactions occurring in 1 of 3500 cases. In such cases, cardiovascular collapse typically occurs within 4 minutes, urging for epinephrine and volume resuscitation [14].

Such problems make suboptimal treatment (underdiagnosed or overdiagnosed with unneeded reversal) account for preventable complications. Increasing the importance of these phenomena is the observed prolonged times of action of NMB agents in elderly populations [10]. Our study made a subanalysis demonstrating that patients under 65 behave as reported in theory with an effect of at least 60 minutes, while in our series, almost 74.51% of them exceeded 90 minutes. Nevertheless, none of the patients above 65 had below 90 minutes of deep NMB, with most of them having residual NMB (50.0 to 83.33% using TOFR criteria < 90 and < 1.00, respectively). Our series demonstrated these patients to have a 6.08-fold OR for increased residual NMB effect and are the population at higher risk of complications by this means derived from their age and comorbidities. The present study aids in demonstrating a significant increase in the rate of underdiagnosed residual NMB. For this reason, we should encourage the development of specific surveillance protocols and actions for this population to prevent significant complications, including the use of shorter-action NMB, early reversal, and prolonged surveillance in the postoperative period. Furthermore, we recommend improving quality control measures, including verifying device calibration and taking as much time as needed to have a trustable instrument.

Limitations, given the retrospective nature of the findings and the small sample size, we could not verify the process of TOF Baseline calibrations; nevertheless, it is a routine in our service practice.

Conclusions

The rate of residual NMB in our practice was in the range of 29.9 to 49.1% depending on the criteria used (TOFR < 0.91 or TOFR < 1.00, respectively), more probably the higher limit, in line with literature ranges. We do recommend extubating patients based on a TOFR criterion of 1.00, especially on the elderly, to avoid clinically relevant residual NMB or its complications. Patients above 65 years old are at an increased risk of residual NMB (6.08 OR) due to increased length of action, as demonstrated by the curves of NMB during surgery. Older patients also had an increased risk (OR 11.75) of clinical symptoms related to the residual neuromuscular block. Therefore, we recommend providing specific surveillance protocols for patients above 65 years-old, including the use of shorter-action NMB, early reversal, and prolonged surveillance in the postoperative period. In addition, we recommend the use of reversal agents in patients at high risk of residual neuromuscular block, such as patients above 65 years-old, especially in those cases where patients have difficultness for reaching a TOFR criterion of 1.00 because of an increased risk of residual neuromuscular block and its complications. We will look to develop future research prospectively to corroborate these results.