Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision.

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59-74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51, 789-808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.

Quantitative Neuromuscular Monitoring and Postoperative Outcomes: A Narrative Review.

Over the past five decades, quantitative neuromuscular monitoring devices have been used to examine the incidence of postoperative residual neuromuscular block in international clinical practices, and to determine their role in reducing the risk of residual neuromuscular block and associated adverse clinical outcomes. Several clinical trials and a recent meta-analysis have documented that the intraoperative application of quantitative monitoring significantly reduces the risk of residual neuromuscular blockade in the operating room and postanesthesia care unit. In addition, emerging data show that quantitative monitoring minimizes the risk of adverse clinical events, such as unplanned postoperative reintubations, hypoxemia, and postoperative episodes of airway obstruction associated with incomplete neuromuscular recovery, and may improve postoperative respiratory outcomes. Several international anesthesia societies have recommended that quantitative monitoring be performed whenever a neuromuscular blocking agent is administered. Therefore, a comprehensive review of the literature was performed to determine the potential benefits of quantitative monitoring in the perioperative setting.

Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Despite application of multimodal pain management strategies, patients undergoing spinal fusion surgery frequently report severe postoperative pain. Methadone and ketamine, which are N-methyl-d-aspartate receptor antagonists, have been documented to facilitate postoperative pain control. This study therefore tested the primary hypothesis that patients recovering from spinal fusion surgery who are given ketamine and methadone use less hydromorphone on the first postoperative day than those give methadone alone. METHODS: In this randomized, double-blind, placebo-controlled trial, 130 spinal surgery patients were randomized to receive either methadone at 0.2 mg/kg (ideal body weight) intraoperatively and a 5% dextrose in water infusion for 48 h postoperatively (methadone group) or 0.2 mg/kg methadone intraoperatively and a ketamine infusion (0.3 mg · kg-1 · h-1 infusion [no bolus] intraoperatively and then 0.1 mg · kg-1 · h-1 for next 48 h [both medications dosed at ideal body weight]; methadone/ketamine group). Anesthetic care was standardized in all patients. Intravenous hydromorphone use on postoperative day 1 was the primary outcome. Pain scores, intravenous and oral opioid requirements, and patient satisfaction with pain management were assessed for the first 3 postoperative days. RESULTS: Median (interquartile range) intravenous hydromorphone requirements were lower in the methadone/ketamine group on postoperative day 1 (2.0 [1.0 to 3.0] vs. 4.6 [3.2 to 6.6] mg in the methadone group, median difference [95% CI] 2.5 [1.8 to 3.3] mg; P < 0.0001) and postoperative day 2. In addition, fewer oral opioid tablets were needed in the methadone/ketamine group on postoperative day 1 (2 [0 to 3] vs. 4 [0 to 8] in the methadone group; P = 0.001) and postoperative day 3. Pain scores at rest, with coughing, and with movement were lower in the methadone/ketamine group at 23 of the 24 assessment times. Patient-reported satisfaction scores were high in both study groups. CONCLUSIONS: Postoperative analgesia was enhanced by the combination of methadone and ketamine, which act on both N-methyl-d-aspartate and µ-opioid receptors. The combination could be considered in patients having spine surgery.

Comparison of the TetraGraph and TOFscan for monitoring recovery from neuromuscular blockade in the Post Anesthesia Care Unit.

STUDY OBJECTIVE: Comparison of the TetraGraph (TG) and TOFscan (TS) for monitoring recovery from neuromuscular blockade in the Post Anesthesia Care Unit (PACU). DESIGN: Randomized, multicenter trial. SETTING: PACU in three tertiary care hospitals. PATIENTS: 120 patients (40 per site) receiving neuromuscular blockade during elective surgery. INTERVENTIONS: Patients were enrolled preoperatively and intraoperative neuromuscular blockade management was at the discretion of the anesthesiologist. Upon arrival to the PACU, patients were randomized to have either TG or TS placed on their dominant hand. The alternate device (TS or TG) was placed on the non-dominant hand. Following simultaneous ulnar nerve stimulation on each arm, the response of the adductor pollicis was measured. MEASUREMENTS: Train-of-four ratios (TOFRs) were obtained upon arrival to the PACU (t = 0), after 5 min (t = + 5) and after +10 min (t = + 10). MAIN RESULTS: There was there was no significant difference in the mean TOFRs obtained with the TG and TS at t = 0 (0.97 ± 0.18 vs 0.94 ± 0.13, P = 0.06, respectively) and t = + 5 (0.96 ± 0.20 vs 0.95 ± 0.12, P = 0.29, respectively). At (t = + 10), there was a statistically significant difference in mean TOFRs obtained with the TG and TS, (0.99 ± 0.14 vs 0.94 ± 0.12, P < 0.001, respectively). The bias between devices at t = 0 was estimated to be 0.03 (95% CI, -0.29 to 0.35, P = 0.26); at t = + 5 min, it was estimated to be 0.02 (95% CI, -0.36 to 0.40, P = 0.54); and at t = +10 min, it was estimated to be 0.05 (95% CI, -0.25 to 0.36, P = 0.77). CONCLUSIONS: TS and TG provide interchangeable quantitative measurements once the TOF ratio has returned to a value of 0.90 or greater in the PACU.

Neuromuscular and Clinical Recovery in Thoracic Surgical Patients Reversed With Neostigmine or Sugammadex.

BACKGROUND: Patients undergoing thoracoscopic procedures may be at high-risk for incomplete neuromuscular recovery and associated complications. The aim of this clinical investigation was to assess the incidence of postoperative residual neuromuscular blockade in adult thoracic surgical patients administered neostigmine or sugammadex when optimal dosing and reversal strategies for these agents were used. The effect of choice of reversal agent on hypoxemic events and signs and symptoms of muscle weakness were also determined. Additionally, operative conditions in each group were graded by surgeons performing the procedures. METHODS: Two hundred patients undergoing thoracoscopic surgical procedures were enrolled in this nonrandomized controlled trial. One hundred consecutive patients maintained at moderate levels of neuromuscular blockade were reversed with neostigmine (neostigmine group) followed by 100 consecutive patients given sugammadex to antagonize deeper levels of neuromuscular blockade (sugammadex group). Anesthetic and neuromuscular management were standardized. Surgeons rated operative conditions at the conclusion of the procedure on a 4-point scale (grade 1 = excellent to grade 4 = poor). Train-of-four ratios were measured immediately before extubation and at PACU admission (primary outcomes). Postoperatively, patients were assessed for adverse respiratory events and 11 signs and 16 symptoms of muscle weakness. RESULTS: The 2 groups were similar in intraoperative management characteristics. The percentage of patients with residual neuromuscular blockade, defined as a normalized train-of-four ratio <0.9, was significantly greater in the neostigmine group than the sugammadex group at both tracheal extubation (80% vs 6%, respectively, P < .0001) and PACU admission (61% vs 1%, respectively, P < .0001). Patients in the neostigmine group had less optimal operative conditions (median score 2 [good] versus 1 [excellent] in the sugammadex group; P < .0001), and more symptoms of muscle weakness were present in these subjects (median number [interquartile range] 4 [1-8] vs 1 [0-2] in the sugammadex group, P < .0001). No differences between groups in adverse airway events were observed. CONCLUSIONS: Despite the application of strategies documented to reduce the risk of residual neuromuscular blockade, a high percentage of thoracoscopic patients whose neuromuscular blockade was reversed with neostigmine were admitted to the PACU with clinical evidence of residual paralysis. In contrast, muscle weakness was rarely observed in patients whose neuromuscular blockade was antagonized with sugammadex.

Postoperative Pain and Analgesic Requirements in the First Year after Intraoperative Methadone for Complex Spine and Cardiac Surgery.

BACKGROUND: Methadone is a long-acting opioid that has been reported to reduce postoperative pain scores and analgesic requirements and may attenuate development of chronic postsurgical pain. The aim of this secondary analysis of two previous trials was to follow up with patients who had received a single intraoperative dose of either methadone or traditional opioids for complex spine or cardiac surgical procedures. METHODS: Preplanned analyses of long-term outcomes were conducted for spinal surgery patients randomized to receive 0.2 mg/kg methadone at the start of surgery or 2 mg hydromorphone at surgical closure, and for cardiac surgery patients randomized to receive 0.3 mg/kg methadone or 12 µg/kg fentanyl intraoperatively. A pain questionnaire assessing the weekly frequency (the primary outcome) and intensity of pain was mailed to subjects 1, 3, 6, and 12 months after surgery. Ordinal data were compared with the Mann-Whitney U test, and nominal data were compared using the chi-square test or Fisher exact probability test. The criterion for rejection of the null hypothesis was P < 0.01. RESULTS: Three months after surgery, patients randomized to receive methadone for spine procedures reported the weekly frequency of chronic pain was less (median score 0 on a 0 to 4 scale [less than once a week] vs. 3 [daily] in the hydromorphone group, P = 0.004). Patients randomized to receive methadone for cardiac surgery reported the frequency of postsurgical pain was less at 1 month (median score 0) than it was in patients randomized to receive fentanyl (median score 2 [twice per week], P = 0.004). CONCLUSIONS: Analgesic benefits of a single dose of intraoperative methadone were observed during the first 3 months after spinal surgery (but not at 6 and 12 months), and during the first month after cardiac surgery, when the intensity and frequency of pain were the greatest.

Awake Volunteer Pain Scores During Neuromuscular Monitoring.

BACKGROUND: There is a need for easy to use, reliable neuromuscular monitors (NMMs). This multicenter, prospective, unblinded study compared the discomfort associated with neurostimulation in unmedicated healthy volunteers when using the new electromyography (EMG)-based TetraGraph and acceleromyography (AMG)-based TOF-Watch NMMs. The secondary aim was to compare the repeatability of the train-of-four (TOF) ratios (TOFRs) obtained with the 2 devices. METHODS: The TOF measurements of 135 volunteers from 3 university hospitals were analyzed (age: 38.3 ± 12 years [mean ± standard deviation [SD]]; male/female ratio = 63:72). The left or right ulnar nerve was stimulated at the wrist in TOF mode with 20, 30, 40, and 50 mA stimulating current intensities with both devices in random order. The TOF-Watch used standard electrocardiography (ECG) electrodes (Red Dot; 3M Health Care) for nerve stimulation. The stimulating surface area of 1 ECG electrode is 113 mm. The piezoelectric probe was attached to the thumb, and a hand adapter was used to ensure consistency of AMG measurements. The TetraGraph uses proprietary surface strip electrodes for nerve stimulation and muscle action potential recording, whose stimulating surface area is roughly twice as big as that of standard ECG electrodes (228.5 mm). The volunteers were asked to rate the discomfort associated with neurostimulation on a 0-10 verbal numerical rating scale (VNRS) score anchored with 0 (no pain) and 10 (worst pain ever experienced). A linear mixed-effects model was used to evaluate the difference in VNRS scores between devices. P <.05 was accepted as the level of significance. RESULTS: In the linear mixed-effects model, there were no differences in VNRS scores between devices at any of the stimulating current intensities, P = .38. The median (range) VNRS scores obtained with TOF-Watch and TetraGraph devices were 2 (0-7) vs 2 (0-8) at 20 mA, 3 (1-9) vs 3 (1-9) at 30 mA, 5 (1-10) vs 5 (1-10) at 40 mA, and 5 (1-10) vs 6 (1-10) at 50 mA stimulating current intensities. The mean of the 1469 TOFRs obtained with TetraGraph was 100.43% ± 7.74% (standard error = 0.2%). Due to technical difficulties, the repeatability of the TOFRs could not be determined. CONCLUSIONS: Despite the different size and design of the stimulating electrodes, the 2 NMMs caused the same level of discomfort in unmedicated healthy volunteers.

Safety of Beach Chair Position Shoulder Surgery: A Review of the Current Literature.

Although uncommon, severe neurological events have been reported in patients undergoing shoulder surgery in the beach chair position. The presumed etiology of central nervous system injury is hypotension and subsequent cerebral hypoperfusion that occurs after alterations in positioning under general anesthesia. Most clinical trials have demonstrated that beach chair positioning results in reductions in regional brain oxygenation, cerebral blood flow, and jugular bulb oxygenation, as well as impairment in cerebral autoregulation and electroencephalographic/processed electroencephalographic variables. Further studies are needed to define the incidence of adverse neurological adverse events in the beach chair position, identify the best intraoperative neurological monitors that are predictive of neurocognitive outcomes, the lowest "safe" acceptable blood pressure during surgery for individual patients, and the optimal interventions to treat intraoperative hypotension.

Comparison of the TOFscan and the TOF-Watch SX during Recovery of Neuromuscular Function.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Quantitative neuromuscular monitoring is required to ensure neuromuscular function has recovered completely at the time of tracheal extubation. The TOFscan (Drager Technologies, Canada) is a new three-dimensional acceleromyography device that measures movement of the thumb in multiple planes. The aim of this observational investigation was to assess the agreement between nonnormalized and normalized train-of-four values obtained with the TOF-Watch SX (Organon, Ireland) and those obtained with the TOFscan during recovery from neuromuscular blockade. METHODS: Twenty-five patients were administered rocuronium, and spontaneous recovery of neuromuscular blockade was allowed to occur. The TOFscan and TOF-Watch SX devices were applied to opposite arms. A preload was applied to the TOF-Watch SX, and calibration was performed before rocuronium administration. Both devices were activated, and train-of-four values were obtained every 15 s. Modified Bland-Altman analyses were conducted to compare train-of-four ratios measured with the TOFscan to those measured with the TOF-Watch SX (when train-of-four thresholds of 0.2 to 1.0 were achieved). RESULTS: Bias and 95% limits of agreement between the TOF-Watch SX and the TOFscan at nonnormalized train-of-four ratios between 0.2 and 1.0 were 0.021 and -0.100 to 0.141, respectively. When train-of-four measures with the TOF-Watch SX were normalized, bias and 95% limits of agreement between the TOF-Watch SX and the TOFscan at ratios between 0.2 and 1.0 were 0.015 and -0.097 to 0.126, respectively. CONCLUSIONS: Good agreement between the TOF-Watch SX with calibration and preload application and the uncalibrated TOFscan was observed throughout all stages of neuromuscular recovery.

Neostigmine Administration after Spontaneous Recovery to a Train-of-Four Ratio of 0.9 to 1.0: A Randomized Controlled Trial of the Effect on Neuromuscular and Clinical Recovery.

BACKGROUND: When a muscle relaxant is administered to facilitate intubation, the benefits of anticholinesterase reversal must be balanced with potential risks. The aim of this double-blinded, randomized noninferiority trial was to evaluate the effect of neostigmine administration on neuromuscular function when given to patients after spontaneous recovery to a train-of-four ratio of 0.9 or greater. METHODS: A total of 120 patients presenting for surgery requiring intubation were given a small dose of rocuronium. At the conclusion of surgery, 90 patients achieving a train-of-four ratio of 0.9 or greater were randomized to receive either neostigmine 40 µg/kg or saline (control). Train-of-four ratios were measured from the time of reversal until postanesthesia care unit admission. Patients were monitored for postextubation adverse respiratory events and assessed for muscle strength. RESULTS: Ninety patients achieved a train-of-four ratio of 0.9 or greater at the time of reversal. Mean train-of-four ratios in the control and neostigmine groups before reversal (1.02 vs. 1.03), 5 min postreversal (1.05 vs. 1.07), and at postanesthesia care unit admission (1.06 vs. 1.08) did not differ. The mean difference and corresponding 95% CI of the latter were -0.018 and -0.046 to 0.010. The incidences of postoperative hypoxemic events and episodes of airway obstruction were similar for the groups. The number of patients with postoperative signs and symptoms of muscle weakness did not differ between groups (except for double vision: 13 in the control group and 2 in the neostigmine group; P = 0.001). CONCLUSIONS: Administration of neostigmine at neuromuscular recovery was not associated with clinical evidence of anticholinesterase-induced muscle weakness. VISUAL ABSTRACT: An online visual overview is available for this article.(Figure is included in full-text article.).

Neuromuscular Monitoring in the Perioperative Period.

Neuromuscular monitoring devices were introduced into clinical practice in the 1970s. Qualitative neuromuscular monitors, or peripheral nerve stimulators, provide an electrical stimulus to a motor nerve and the response of corresponding muscle subjectively evaluated. A standard peripheral nerve stimulator provides several patterns of nerve stimulation, including train-of-four (TOF), double-burst, tetanic, and post-tetanic count. Qualitative (and quantitative) monitors are needed to determine onset of neuromuscular blockade, maintain the required depth of muscle relaxation during the surgical procedure, and assess an appropriate dose of reversal agent. However, absence of fade measured with a peripheral nerve stimulator does not exclude residual neuromuscular block; TOF ratios as low as 0.4-0.6 may be present when fade is no longer observed. In addition, the risk of incomplete neuromuscular recovery may be influenced by monitoring site. The adductor pollicis is more sensitive to the effects of neuromuscular blocking agents (compared to the muscles surrounding the eye), and monitoring at this site may more accurately reflect recovery of pharyngeal muscles (the last muscles to recover from the effects of neuromuscular blocking agents, in which dysfunction may persist even at a TOF ratio of 1.0). Quantitative monitors are devices that measure and quantify the degree of muscle weakness and display the results numerically. Several different technologies have been developed, including mechanomyography, electromyography, acceleromyography, kineograph, and phonomyography. Lower doses of anticholinesterases may be used to effectively reverse neuromuscular blockade at TOF ratios of 0.4-0.6; quantitative monitoring is required to determine that this level of neuromuscular recovery has occurred. As clinical tests of muscle strength, peripheral nerve stimulators are unable to determine whether full recovery of neuromuscular function is present at the end of the surgical procedure. The use of quantitative monitors is essential in excluding clinically important muscle weakness (TOF ratios <0.9 to 1.0) at the time of tracheal extubation.

Procedural Timeout Compliance Is Improved With Real-Time Clinical Decision Support.

PURPOSE: The goal of this study was to assess compliance with a presurgical safety checklist before and after the institution of a surgical flight board displaying a surgical safety checklist with embedded real-time clinical decision support (CDS). We hypothesized that the institution of a surgical flight board with embedded real-time data support would improve compliance with the presurgical safety checklist. METHODS: In this prospective, observational trial, surgeon-led procedural timeout compliance for 300 procedures was studied. In phase I (PI), procedural timeouts were performed using a simple paper checklist. In phase II (PII), an electronic surgical flight board with an embedded safety checklist was installed in each operating room, but the timeout procedure consisted of the same paper process as in PI. In phase III (PIII), the flight board safety checklist was used. Ten procedures each from 10 surgeons were evaluated in each phase. Compliance was scored on a 12-point scale with each point representing a different item on the checklist. RESULTS: Timeout compliance in PI ranged from 4.5 to 8.6 and 8.75 to 12 in PIII. All 10 surgeons demonstrated statistically improved compliance from PI to PIII. Compliance was significantly improved in 8 of 12 safety check items. Decreased compliance was not seen with any checklist item. Of the items with CDS, compliance with procedure consent and special safety precautions improved from PI to PIII, as did compliance with display of essential imaging, critical events or concerns, and number of procedures (i.e., >1 surgeon performing procedures). CONCLUSIONS: Using the electronic medical record with real-time CDS improves compliance with presurgical safety checklists.

Postoperative Intravenous Acetaminophen for Craniotomy Patients: A Randomized Controlled Trial.

OBJECTIVE: To determine whether opioids during the first 24 postoperative hours were significantly altered when receiving intravenous (IV) acetaminophen during that time compared with those receiving placebo (normal saline). METHODS: One hundred forty patients undergoing any type of craniotomy were randomly assigned to receive either 1 g of IV acetaminophen or placebo upon surgical closure, and every 6 hours thereafter, up to 18 hours postoperatively. Analgesic requirements for the first 24 postoperative hours were recorded. Time to rescue medications in the postanesthesia care unit (PACU)/intensive care unit (ICU), amount of rescue medication, ICU and hospital lengths of stay, number of successful neurological examinations, sedation, delirium, satisfaction, and visual analog scale pain scores were also recorded. RESULTS: Compared with the placebo group, more patients in the IV acetaminophen group (10/66 [15.2%] vs. 4/65 [6.2%] in the placebo group) did not require opioids within the first 24 postoperative hours, but this did not reach significance (odds ratio, -9.0%, 95% confidence interval -20.5% to 1.8%; P = 0.166). Both groups had similar times to rescue medications, amounts of rescue medications, ICU and hospital lengths of stay, numbers of successful neurological examinations, sedation, delirium, satisfaction scores, visual analog scale pain scores, and temperatures within the first 24 postoperative hours. CONCLUSIONS: The opioid requirements within the first 24 postoperative hours were similar in the placebo and acetaminophen groups. This study is informative for the design and planning of future studies investigating the management of postoperative pain in patients undergoing craniotomies.