Lambert-Eaton Myasthenic Syndrome

This is a platform study and is governed by a single master protocol that enables multiple regimens to be evaluated in separate intervention-specific appendixes (ISAs). The key design structure of the platform study comprises: common master protocol screening period, ISA-specific screening period, ISA treatment period of variable duration and design and ISA safety follow-up/follow-up period of variable duration. Details on each study period will be specified in the ISAs. Following ISAs are included in this platform study: * NCT07284420 - ADAPT Forward 1 - a study to evaluate empasiprubart IV as add-on therapy to efgartigimod IV in participants with AChR-Ab seropositive generalized myasthenia gravis with a partial clinical response to efgartigimod (https://www.clinicaltrials.gov/study/NCT07284420)

Once the master protocol and ISA1 screening periods are completed, eligible participants can enroll in the run-in period (part A) where they will receive efgartigimod IV. Eligible participants can then continue to the add-on period (part B) where they will receive both efgartigimod IV and empasiprubart IV. Participants who are not eligible for part B will continue directly to the safety follow-up period (part C) where they will receive efgartigimod IV only. The study duration for each participant is approximately up to 54 weeks.

Introduction Residual neuromuscular blockade is a common occurrence in the post-anesthesia care unit (PACU) when neuromuscular blocking agents (NMBAs) have been used in the operating room. The only method of reliably detecting residual neuromuscular blockade is through the use of quantitative neuromuscular monitors. Unfortunately, several barriers exist that have prevented the widespread use of these devices. For instance, there is a paucity of quantitative neuromuscular monitors commercially available. Also, two modalities of quantitative monitoring, kinemyography and acceleromyography, rely on movement of the muscles of interest, a characteristic frequently compromised during patient positioning for surgical procedures in which the patient's arms are secured under surgical drapes (laparoscopic, bariatric, robotic, spine, and neurosurgical procedures) or in uncooperative awake patients in the PACU or intensive care unit (ICU). The aim of this investigation is to determine the different muscle sensitivities to NMBA and reversal agents by comparing responses at two different monitoring sites as measured with a new quantitative monitor. EMG measures electrical activity within the muscle following peripheral nerve stimulation and is unaffected by involuntary patient motion or by restricted muscle movements from surgical positioning. We plan to compare measurements obtained with two TetraGraph devices, one monitoring the adductor pollicis (thumb) muscle and the other monitoring adductor digiti minimi (5th digit) muscle, during onset, maintenance, and recovery of neuromuscular blockade. This will include monitoring every 20 sec for onset of blockade (defined as time from Train-of-Four ratio, TOFR=1.0 until Train-of-four count, TOFC=0) following rocuronium administration, during maintenance of neuromuscular block as required by surgical conditions, and following reversal administration until adequate recovery is documented (train-of-four ratio, TOFR ≥0.9). Medication of the patient, surgical procedure Upon entering the operating room, all patients underwent monitoring using electrocardiograms, noninvasive blood pressure measurements, and pulse oximetry. An intravenous catheter was inserted into either the forearm or the dorsal vein. Anesthesia was initiated with intravenous fentanyl (2.0 mg/kg) and propofol (1.5 to 2.5 mg/kg) and was maintained using sevoflurane (end-tidal concentration of 1.0 to 1.3%) in an air-oxygen mixture, with additional fentanyl given as needed. Before tracheal intubation, the patients were manually ventilated with 100% oxygen via facemask. Oxygen saturation was kept above 96%, and normocapnia was maintained. A forced air warming system (Bair Hugger, Arizant Healthcare Inc., Eden Prairie, Minnesota, USA) was used to keep the body temperature at or above 36°C. Intraoperative hypotension was treated with ephedrine, norepinephrine, or a fluid bolus, according to clinical indications. Ondansetron 4mg IV was routinely administered to prevent postoperative nausea and vomiting. Neuromuscular Management Before the induction of anesthesia, after appropriate skin cleaning, single-use surface TetraGraph electrodes were placed over the ulnar nerve and thumb to assess the adductor pollicis response on one hand, and over the ulnar nerve and fifth digit to assess the abductor digiti minimi response on the other hand. Following the induction of anesthesia, train-of-four (TOF) stimulation was applied to both muscle groups at a frequency of 2 Hz for 1.5 seconds every 15 seconds, after the automated calibration of supramaximal current and responses. Once stable baseline TOF responses were established, all patients received 0.6 mg/kg of rocuronium intravenously. Measurements were taken every five minutes during the intraoperative period until the administration of sugammadex. After that, we monitored the spontaneous recovery of the rocuronium-induced neuromuscular block until three consecutive TOF counts of 2 (TOFC2) were observed at both monitoring sites. Additional doses of rocuronium (0.1-0.2 mg/kg) were administered as necessary to maintain a Train of Four (TOF) count of ≤2. At the end of the surgery, sugammadex was given at a dose of 2 mg/kg. After administering sugammadex, measurements were taken every 20 seconds until the patient was extubated. Following the measurements obtained with both devices at the specified intervals, and once the TOF ratio exceeded 0.9, the devices were disconnected, and the patients continued along the standard recovery pathway. Rescue medication After pharyngoscopy, rescue medication is given if necessary, i.e. below 90% TOF, depending on the type of muscle relaxant used. If an aminosteroid muscle relaxant is used, the patient is given 2 mg/kg sugammadex, while if a benzylisoquinoline muscle relaxant is used, 0.05 mg/kg neostigmine and 0.015 mg/kg atropine are administrated to antagonise the drug effect.

A quantitative neuromuscular monitoring device is desirable to titrate the depth of neuromuscular block (NMB) during a procedure, and to prevent residual effects after removal of the endotracheal tube. Unfortunately, the most widely used monitoring technique acceleromyography (AMG) typically implies a series of cumbersome installation and calibration procedures that frequently precludes correct use of these devices in clinical practice. Electromyography (EMG) has recently attracted a lot of attention as an alternative strategy to compensate for the deficiency of AMG-based neuromuscular monitors. Nowadays, a new technology that allows for the simultaneous acquisition of EMG and AMG signals is commercially available. Although its reliability has been rapidly accepted in Physical Medicine and Rehabilitation, the use of the technique in neuromuscular monitoring has never been reported. The aim of the present study is to assess the validity of the new device for estimating the neuromuscular block by comparing with TOF Watch®-SX, which is the most widely accepted AMG-based neuromuscular monitor that has been practiced in the clinical arena for decades.

The development of advanced competence in laparoscopic surgery, robotic surgery and the broadening of indications for partial or total laparoscopy techniques created a novel environment where patients need to be deeply paralyzed and positioned in form fitting mattresses to ensure high quality exposure and security in extreme positioning. It is now undisputed that clinical evaluation done any other way than by a objective neuromuscular function monitor may produce faulty conclusions. The elements of the operating setup force anesthesiologists to adapt the way they monitor muscle relaxation since the hands are generally not available for neuromuscular function monitoring. In order to measure properly the level of residual paralysis, the thumb must be able to move freely in a device creating a light preloading on the adductor pollicis allowing to evaluate the force generated during standardized stimulation through accelerometry, the TOFscan device. The corrugator supercilli and orbicularis oculi muscles, an alternate positioning for the accelerometer is sometimes the fallback spot for monitoring. The problem with that muscle is that it does not have the same time curve sensitivity to muscle relaxant than the perilaryngeal muscle have. The investigators are looking for a good representation of the level of patency of the perilaryngeal muscle to ensure that the patient will be able to breath normally after extubation, they must turn to another target. Previous observations have suggested that the monitoring of the hallux flexor muscle could represent a valid alternative. The confirmation of this hypothesis would allow for easy, reproducible, evaluation of the level of muscle relaxation at the perilaryngeal muscles, helping to procure safer conditions for tracheal extubation. Neuromuscular blocking agents (NMBAs) are administered by anesthesiologists during general anesthesia to facilitate endotracheal intubation and/or surgical conditions. Postoperative residual neuromuscular blockade (rNMB), is an adverse event frequently observed after extubation in the postanesthesia care unit (PACU) after surgery. rNMB is associated with upper airway obstruction, reduced pharyngeal muscle coordination, decreased functional residual capacity, and impaired hypoxic ventilatory response and may lead to critical cardiopulmonary complications. To prevent those complications, monitoring NMBAs activity and timely and adequate dosage of reversal agents necessitate precise and valid monitoring. The current literature supports the exclusive use of quantitative measurements of residual paralysis, subjective monitoring caries to much error in evaluating the level of blockade and is responsible for PACU residual paralysis and its complications. It is well accepted that no amount of rNMB is acceptable (TOF \< 1) around extubation periods, a necessary step to ensure safety that relies on timely and correct dosage of the reversal agents. When TOFscan measures are done on partially mobile thumbs, or transducers positioned in non-optimal fashion, the measure observed (deep blockade) will either delay the reversal procedure because of presumed very deep level paralysis or suggest high doses of reversal agents at a significant cost. The investigators are confident that validating the measures done at the hallux flexor will allow for easy, relevant and valid estimation of residual paralysis and create a safer environment for muscle relaxation reversal and extubation.

Neuromuscular blockers (NMB) agents are commonly used drugs in anesthesia for facilitating airway management, improving surgical conditions, and inducing immobility in critical situations. As a natural consequence of their use, postoperative residual neuromuscular block has been associated with serious postoperative complications such as upper airway obstruction, reintubation, atelectasis, pneumonia, prolonged stay in the post-anesthesia care unit (PACU), and decreased patient satisfaction. The incidence of residual block at the end of surgery and/or in the PACU is approximately 64% according to the literature . Various factors contribute to the high incidence of residual neuromuscular block, including variability in the duration of action of neuromuscular blocker agents, variability in the time it takes for antagonist drugs to restore neuromuscular function, and clinicians' reliance on unreliable methods for assessing neuromuscular strength, such as continuous head lifting, grip strength, or respiratory measurements (e.g., tidal volume, inspiratory force), and the subjective evaluation of peripheral nerve stimulation responses . Residual neuromuscular block is a significant patient safety concern, and its detection and risk reduction are crucial for improving patient outcomes. One of the objective methods for assessing neuromuscular function is the Train of Four (TOF), which is an acceleromyographic peripheral nerve stimulator. The effectiveness of TOF as an objective and quantitative assessment of neuromuscular block and its role in reducing postoperative complications has been demonstrated in numerous studies. In 2023, the "American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade" presented it with a moderate level of evidence and a high recommendation level. Likewise, in 2023, the European Society of Anesthesiology and Intensive Care's "Perioperative Management of Neuromuscular Blockade" guideline recommended TOF monitoring as part of routine perioperative monitoring with a 1B level of evidence . TOF involves delivering four brief electrical impulses to a peripheral nerve at a frequency of 2 Hz and evaluating the resulting "twitches." The ratio of the response to the fourth stimulus to the response to the first stimulus (T4/T1) is referred to as the TOF ratio. Acceptable recovery of neuromuscular function is defined as a TOF ratio greater than or equal to 0.9. In a prospective study conducted in 2022 by Schmartz and colleagues, they compared a modified TOF ratio (T4/Tr) to the classic TOF ratio (T4/T1) against a reference measurement and demonstrated that the T4/Tr ratio is a better indicator of readiness for adequate recovery and safe extubation from non-depolarizing neuromuscular blockade compared to the classic TOF ratio (T4/T1) . This result suggests that the classic TOF ratio may overestimate the degree of true neuromuscular recovery, potentially leading to early tracheal extubation, increased risk of postoperative pulmonary complications, and endangering patient safety. The aim of our study is to determine whether the differences in mTOF/classic TOF durations, as shown by Schmartz and colleagues in spontaneous neuromuscular recovery, also result in significant differences when rocuronium is reversed with sugammadex. PROTOCOL: Consent will be obtained from patients who meet the inclusion criteria during preoperative evaluation. After being admitted to the operating room, demographic information will be recorded and the following steps will be routinely performed. Monitoring: ECG + NIKB + SpO2 + BIS + acceleromyography + body temperature Premedication: 1 mic/kg fentanyl and 0.05 mg/kg midazolam Preoxygenation: 3 minutes using 80% oxygen + 20% air with mask Anaesthesia Induction: 1 mic/kg fentanyl + 1 mg/kg lidocaine + 1 mg/kg propofol (BIS-guided) + 0.5 mic/kg breviblock Neuromuscular monitoring: After all standard preparations Set current to 50 mA Cancel T4/T2 TOF warning (1-2 times) 50 Hz tetanic stimulation for 5 s Calibration TOF warning until stabilisation is achieved (TOFr changes by less than 5% for 2-5 minutes) Muscle relaxation 1 mg/kg (according to ABW, actual) rocuronium/5 s bolus Analgesia 1 mic/kg fentanyl Intubation: Intubation with appropriately sized ETT when BIS is between 40-60, cTOFR: 0% Maintenance: BIS-guided TIVA anaesthesia (total 1 l/min oxygen and air mixture with FiO2 with SpO2 between 95-98) Muscle relaxant maintenance: PTC is measured at 5 minute intervals. PTC 1-2 is targeted. 5 mic/kg/min infusion is started. PTC measurement is continued. When PTC is 0, muscle relaxant infusion is stopped. Intraoperative follow-up: PTC is measured at 5 minute intervals * Stop rocuronium infusion if PTC is 0 * PTC 1-2 targeted values, 5 mic/kg/min maintenance rocuronium infusion is started. * If PTC increases to 3 and above, 0.1 mg/kg bolus dose is added to the infusion. At the end of surgery : Anaesthetic drugs are switched off. PTC : 1-2, cTOFr measurement is started at 15 s intervals. 4 mg/kg sugammadex is administered. If cTOFR does not increase to 90% and above within 5 minutes, an additional dose of neostigmine is administered (0.02 mg/kg dose, without atropine). Extubation: Extubation is performed when BIS is above 90% and cTOFR is 90% and above. The patient is followed in the operating room until cTOFR and mTOFR are 100%. During the perioperative course, the patient's TOFscan (cTOFR - mTOFR) data, the amount of neuromuscular blockers used, and the need for reversal medication are recorded. STATISTICAL METHODOLOGY: Sample Size The sample size required for the study was based on the difference between classical TOF and mTOF in neuromuscular recovery with Sugammadex. Accordingly, the required sample size for this study was calculated as 199 when the sample calculation was performed with the paired t test in dependent groups at 80% power and 0.05 significance level for a value of 0.2 indicating a low magnitude effect. GPOWER 3.1 was used for sample calculation. Source: Cohen, J (1988). Statistical Power Analysis for the Social Sciences (2nd. Edition). Hillsdale, New Jersey, Lawrence Erlbaum Associates. Statistical Methods Descriptive statistics will be given as frequency (%) for categorical variables, mean ± standard deviation and median (minimum-maximum) for continuous variables. In the comparison of dependent groups, paired t test will be used when the assumption of normal distribution is met and Wilcoxon test will be used when the assumption of normal distribution is not met. Statistical significance level will be accepted as p\<0.05. The evaluation of the data will be done in SPSS 11.5 for Windows programme.

BACKGROUND: Some studies have revealed that deep neuromuscular block (NMB) improve surgical conditions and alleviated postoperative pain compared with moderate NMB. The present study investigated deep NMB could improve the quality of recovery after laparoscopic hysterectomy METHODS: seventy-two women with elective laparoscopic hysterectomy were randomly divided into 2 groups: Patients in group A received low-pressure pneumoperitoneum (LPP), which was set at 8-10 mmHg with deep NMB. Patients in group B received standard-pressure pneumoperitoneum (SPP), which was set at 12-14 mmHg with moderate NMB. Primary outcome was the quality of recovery (QoR-15) at 1 day after sugery. The secondary outcomes included postoperative pain, surgical condition, incidence of shoulder pain, the incidence of rescue analgesic drug use, cumulative dose of analgesics, time of first flatus, post-operative nausea and vomiting, time of tracheal tube removal.

This study aims to investigate the impact of varying degrees of neuromuscular blockade on postoperative pain in pediatric patients aged over 2 months to under 7 years undergoing laparoscopic surgery under general anesthesia.

In recent years, studies have been published showing that by applying deep neuromuscular block during laparoscopic cholecystectomy, intraabdominal pressure can be reduced without compromising the surgical conditions, thus complications such as postoperative nausea and vomiting (PONV) and pain can be reduced. The results we obtained in our previous study showed that deep neuromuscular block achieved with a high dose of 1.2 mg/kg rocuronium allowed the operation to be performed with lower intra-abdominal pressure values, shortened the operation time, reduced PONV and pain in laparoscopic cholecystectomy cases. The most important factor affecting the depth of neuromuscular block is the dose of the neuromuscular agent. However, anesthetic agents can also affect the depth of neuromuscular blockade. The effects of muscle relaxants are enhanced when administered together with inhalation anesthetics.Propofol and sevoflurane are widely used in the maintenance of anesthesia. Unlike propofol, sevoflurane enhances the effects of some neuromuscular blocking drugs, including rocuronium. Our primary aim in this study is to evaluate the effects of sevoflurane, desflurane, or propofol, which are commonly used in anesthesia maintenance, on the duration of neuromuscular block caused by 1.2 mg/kg rocuronium, which is the dose we routinely use in anesthesia induction, in laparoscopic cholecystectomy cases. Secondary aims are to investigate its effects on intraabdominal pressures and surgical conditions, and to determine whether it reduces postoperative pain and PONV, as well as extubation and recovery times.

Numbers of elderly patients requiring anesthesia and surgery are increasing, and as a group, elderly patients are at high risk of postoperative complications. Aging leads to a progressive impairment of organ function and a decline in physiologic reserve and in the elderly patient population, pharmacodynamics and pharmacokinetics of medications administered during anesthesia may be influenced by the age-related reduction in cardiac output, liver function and renal function. Also, the body composition changes with age and elderly have lower total body water and an increase in body fat. Neuromuscular blocking agents (NMBAs) are administered during anesthesia to facilitate tracheal intubation. However, in elderly patients onset time of standard doses of NMBAs are prolonged, and for 0.6 mg/kg of rocuronium it is prolonged by 50% when comparing elderly with younger adults (median 135 seconds vs 90 seconds). A prolonged onset time of rocuronium may result in prolonged time to tracheal intubation which aims to secure the patients airway and breathing during anesthesia and thereby prevents pulmonary aspiration and hypoxia. It is therefore relevant to investigate measures to reduce onset time of rocuronium in the elderly. Ephedrine administered in younger adults undergoing general anesthesia has reduced the onset time of rocuronium 0.6 mg/kg. The mechanism behind this is speculated to be an increase in cardiac output. It is possible to detect onset time of NMBAs with objective neuromuscular monitoring perioperatively by train-of-four (TOF) stimulation at the ulnar nerve. The effect of ephedrine on onset time of rocuronium has not been assessed in elderly patients above 80 years of age. The possible benefit of this trial is to investigate whether ephedrine 0.15 mg/kg reduces onset time of rocuronium 0.6 mg/kg in the elderly. This may result in a shorter time to tracheal intubation and also establish better intubating conditions. The results may help to detect the optimal method for administering rocuronium to facilitate tracheal intubation in elderly patients. The investigators hypothesize that ephedrine 0.15 mg/kg will provide a shorter onset time of rocuronium compared to placebo (saline).