Deep Blockade Research Articles

Recurarization with magnesium sulfate administered after two minutes sugammadex reversal: A randomized, double-blind, controlled trial

Study objectiveThe current study tested the hypothesis that magnesium sulfate after reversal with sugammadex causes recurarization. DesignA single-center, prospective, randomized, double-blind, controlled trial. SettingTerciary care hospital in Rio de Janeiro, Brazil. PatientsIncluded 60 patients undergoing for elective otolaryngological surgery. InterventionsAll patients received total intravenous anesthesia and a single dose of rocuronium (0.6 mg/kg). In 30 patients, the neuromuscular blockade was reversed with sugammadex (4 mg/kg) at the reappearance of one or two posttetanic counts (deep-blockade series). In 30 other patients, sugammadex (2 mg/kg) was administered at the reappearance of the second twitch of the train-of-four (moderate-blockade series). After the normalized train-of-four ratio recovered to ≥0.9, the patients in each series were randomized to receive intravenous magnesium sulfate (60 mg/kg) or placebo for 10 min. Neuromuscular function was measured by acceleromyography. MeasurementsThe primary outcome was the number of patients who exhibited recurarization (normalized train-of-four ratio < 0.9). The secondary outcome was rescue with an additional dose of sugammadex after 60 min. Main resultsIn the deep-blockade series, a normalized train-of-four ratio < 0.9 occurred in 9/14 (64%) patients receiving magnesium sulfate and 1/14 (7%) receiving placebo, RR 9.0 (95% CI: 62–1.30), and (p = 0.002), with four rescues with sugammadex. In the moderate-blockade series, neuromuscular blockade recurred in 11/15 (73%) patients receiving magnesium sulfate and in 0/14 (0%) receiving placebo (p < 0.001), with two rescues. The absolute differences in recurarization were 57% and 73% in the deep-blockade and moderate-blockade, respectively. ConclusionsSingle-dose magnesium sulfate led to a normalized train-of-four ratio < 0.9, 2 min after recovery from rocuronium-induced deep and moderate neuromuscular blockade using sugammadex. Additional sugammadex reversed prolonged recurarization.

Single-Molecule Investigation of the Protein-Aptamer Interactions and Sensing Application Inside the Single Glass Nanopore.

Solid-state nanopores offer a nanoconfined space for a single-molecule sensing strategy. Evaluating the behavior of proteins and protein-related interactions at the single-molecule level is becoming more and more important for a better understanding of biological processes and diseases. In this work, the aptamer-functionalized nanopore was prepared as the sensing platform for kinetic analysis of the carcinoembryonic antigen (CEA) with its aptamers, which is an important cancer biomarker. CEA molecules were captured by the aptamers immobilized on the inner surface of the nanopore, and there was a complicated interaction between the CEA molecules and the aptamer, which is the process of association and dissociation. This could be used to measure the dynamics of aptamer-protein interactions without labeling. The kinetic analysis could be evaluated at the single-molecule level to interpret the dissociation constants of the binding and dissociation processes. Results showed that the translocation of CEA molecules in a functionalized nanopore had a deep blockades degree and long duration compared with nanopore modified with bare gold, which could be used for CEA sensing. This protein and protein-related interaction we designed provides new insights for evaluating the binding affinity, which will be beneficial for protein sensing and immunoassays.

Cortisol secretory patterns in deep and moderate neuromuscular blockades in laparoscopic surgery under total intravenous anesthesia: A prospective, single-blinded, randomized controlled trial.

Background:Neuroendocrine stress response induces physiological changes depending on the type of surgery and anesthesia. Although the optimal depth of neuromuscular blockade for reducing this response remains unknown, deep neuromuscular blockade is known to improve the surgical environment. Therefore, we hypothesized that a patient’s stress response would be lower in surgical procedures under deep neuromuscular blockade than under moderate neuromuscular blockade.Methods:This prospective, randomized, single-blind study enrolled 72 patients who underwent laparoscopic gynecological surgery under general anesthesia and were assigned to group D (deep blockade: target train-of-four 0 and posttetanic count ≥ 1) or group M (moderate blockade: target train-of-four count 1–3). The primary endpoints were changing patterns in cortisol and adrenocorticotrophic hormone levels; the secondary endpoints were patient outcomes, such as hemodynamic variables, serum glucose level, postoperative pain in the postanesthesia care unit, and hospital stay.Results:The baseline characteristics were comparable between the 67 patients included in the 2 groups (34 in group M and 33 in group D). Cortisol and adrenocorticotrophic hormone levels increased perioperatively in both groups but without significant intergroup differences. Serum glucose level increased perioperatively and decreased postoperatively, but without a significant intergroup difference. Postoperative pain, fentanyl requirement in the postanesthesia care unit, and hospital stay were also comparable.Conclusions:Compared with moderate neuromuscular blockade, deep neuromuscular blockade improved the surgical environment without significant intergroup differences in the hormonal stress response.

Does deep neuromuscular blockade provide improved outcomes in low pressure laparoscopic colorectal surgery? A single blinded randomized pilot study.

Low intra-abdominal pressure during laparoscopic colorectal surgery may improve outcomes and reduce hospital stay, in addition to Enhanced Recovery After Surgery (ERAS) protocols. There is concern that low pressure reduces laparoscopic vision and may increase surgical complications. Deep neuromuscular blockade may abrogate any reduction in vision of low-pressure pneumoperitoneum. However, antagonism of deep neuromuscular blockade at completion of surgery necessitates the use of sugammadex, which is prohibitively expensive, if there are no surgical benefits and warrants further study. A single institution, single blinded randomized controlled pilot study was performed comparing deep to moderate neuromuscular blockade in major laparoscopic colorectal surgery. Thirty-eight patients were randomized to deep or moderate neuromuscular blockade. There were no statistically significant differences between groups, when comparing key patient demographics, or surgeon satisfaction with view, which required increased pressure or further relaxation demands. The deep blockade group had increased QoR15 scores and a decrease in pain, C-Reactive Protein (CRP) measurements and operating times, although were non-significant. The moderate group had slightly higher incidents of Medical Emergency Team (MET) calls and more severe complications, although were non-significant. Low intra-abdominal pressure in laparoscopic colorectal surgery is feasible and allows adequate surgical visualization, regardless of the degree of neuromuscular blockade. Potential benefits of deep neuromuscular blockade may include improved pain and quality of recovery and a possible reduction of complications; however a larger cohort is required to confirm this. Future ERAS protocols may consider deep neuromuscular blockade with low intra-abdominal pressure to further benefit patients.

Sugammadex and Postoperative Pulmonary Complications: Is Stronger Evidence Required?

Sugammadex and Postoperative Pulmonary Complications: Is Stronger Evidence Required?

Reevaluation and update on efficacy and safety of neostigmine for reversal of neuromuscular blockade.

Postoperative residual neuromuscular block is a serious threat which endangers the patient safety. Neostigmine has been the most commonly used anticholinesterase for the pharmacological reversal of neuromuscular blockade. Although newer agents have been introduced recently, neostigmine has some irreplaceable advantages, including broad-spectrum reversal of all nondepolarizing neuromuscular blocking drugs, low cost, and availability of more related data for clinical practice to refer to. Neostigmine is also noticed to have some drawbacks, such as the inability to reverse profound and deep blockade, potential induction of muscle weakness, cardiovascular adverse effects, and so on. Data on the usage of neostigmine in the geriatric and the pediatric population are still insufficient. Some discrepancies are observed in the results from previous studies which need further investigation. However, recent studies offer some renewed information. Regarding both efficacy and safety, the key for successful reversal of neuromuscular blockade is to use neostigmine “appropriately,” optimizing the dosage and timing of administration under close monitoring.

Deep versus moderate neuromuscular block during one-lung ventilation in lung resection surgery

Background and objectivesNeuromuscular relaxants are essential during general anesthesia for several procedures. Classical anesthesiology literature indicates that the use of neuromuscular blockade in thoracic surgery may be deleterious in patients in lateral decubitus position in one-lung ventilation. The primary objective of our study was to compare respiratory function according to the degree of patient neuromuscular relaxation. Secondary, we wanted to check that neuromuscular blockade during one-lung ventilation is not deleterious. MethodsA prospective, longitudinal observational study was made in which each patient served as both treated subject and control. 76 consecutive patients programmed for lung resection surgery in Gregorio Marañon Hospital along 2013 who required one-lung ventilation in lateral decubitus were included. Ventilator data, hemodynamic parameters were registered in different moments according to train-of-four response (intense, deep and moderate blockade) during one-lung ventilation. ResultsPeak, plateau and mean pressures were significantly lower during the intense and deep blockade. Besides compliance and peripheral oxygen saturation were significantly higher in that moments. Heart rate was significantly higher during deep blockade. No mechanical ventilation parameters were modified during measurements. ConclusionsDeep neuromuscular blockade attenuates the poor lung mechanics observed during one-lung ventilation.

In Reply

We read with interest the valuable comments of Schmartz et al ., which require some clarifications.Succinylcholine was used in 14 patients (three in deep blockade [DB] and 11 in moderate blockade [MB]). After excluding patients administered succinylcholine, main data, expressed as median (range) and [percentile 10–90] were total dose of rocuronium (mg), 107.5 (70–290) [85.5–148.7] DB versus 100 (50–180) [68–157] MB, P = 0.169; total dose of sugammadex (mg), 250 (120–520) [200–454] DB versus 150 (100–320) [110–273] MB, P < 0.001; dose of sugammadex per real body weight (mg/kg), 2.30 (1.12–4.42) [1.51–3.925] DB versus 1.2272 (0.88–3.37) [1.0224–2.3638] MB, P < 0.001; time to train-of-four ratio of 0.9 s, 168.5 (20–460) [80–338] DB versus 111.5 (28–300) [49.7–213] MB, P < 0.001. In DB, 16 (40%) patients required a second dose of sugammadex and 14 (21%) in MB, P = 0.047. These results are not different from data presented.1Even if some activity of succinylcholine would be present, it was not determining the results of the study.Sugammadex is able to quickly reverse a neuromuscular blockade (by <2 min); increasing the dose does not hasten recovery.2In our protocol, if the train-of-four ratio was less than 0.9, a second dose of sugammadex was administered after 3 min for DB and 2 min for MB. More than 20% and approximately 40% of patients with MB and DB, respectively, required a second dose. Delayed response to sugammadex is pointed out in most of the publications related to sugammadex administration to lean patients. In addition, the combination of underdose and delayed response has been associated with recurarization.3In favor of safety, tracheal extubation has to be performed when the train-of-four ratio 0.9 target is achieved. A delayed response to sugammadex (target not achieved at the expected time) makes tracheal extubation more challenging, especially in the morbid obese, who are at risk of potential airway serious complications; therefore, requiring close surveillance and neuromuscular monitoring.In the first draft to ANESTHESIOLOGY, “Profound Blockade” was defined as “posttetanic count ≥ 1 to T1 appearance,” literal translation of the text in the observational study protocol (approval reference SAB-SUG-2011-01). Reviewers asked for a better description of DB, so we remade figure 1, modifying the definition of DB by using the number of twitches in the posttetanic count (posttetanic count = 0–12 twitches); however, on the draft we send and in the final draft version, “posttetanic count = 0–2 twitches” were written (this error was also reproduced in the text). This has created difficulty in interpreting methods. We apologize for that. Reviewing our database, all patients with DB had almost one twitch at posttetanic response count; therefore, no patient had intense neuromuscular blockade.Even not significant, slightly more rocuronium was administered to patients with DB (even more after excluding patients administered succinylcholine). As it has been indicated, the interindividual variability to neuromuscular blocking agents is large, even more for rocuronium.4This variability could be facilitated by the association with sevoflurane in our patients.When large doses of rocuronium have been used, we do not know how much rocuronium is still available after sugammadex administration. Redistribution of rocuronium might explain delayed response, or even outliers; however, this statement remains to be demonstrated.Antoni Sabate, M.D., Ph.D.,*Sandra Llaurado, M.D.*Reanimation and Pain Clinic, Hospital Universitari de Bellvitge, Universitat de Barcelona Health Campus, Barcelona, Spain. asabatep@bellvitgehospital.cat

PHP87 Evaluation of Real Life Use of Sugammadex for Decurarization of Neuromuscular Blockade in Surgical Interventions in Belgium

Sugammadex is registered for decurarization of moderate/deep neuromuscular blockade induced by rocuronium or vecuronium. The advantages compared to the well-known decurarization drugs like neostigmine is that undesirable side-effects (bradycardia-bronchoconstriction-hypersalivation-nausea-vomiting) are avoided and deeper levels of blockade can be reversed. In Belgium its reimbursement is restricted to certain conditions (impossible intubation or rapid decurarization of deep blockade when medically required or rapid decurarizaton moderate blockade in patients with obstructions (stomach/bowel, bile duct, urinary tract) or when administration of neostigmine is contra-indicated). The objective of this study was to evaluate Belgian real-life use of sugammadex one year after reimbursement was granted. The medical records of 330 adult patients being treated with sugammadex during the first half year of 2011 (6 hospitals selecting 55 consecutive patients) were retrospectively reviewed. Data collection included baseline patient-characteristics, hospital-, surgery- and sugammadex-related info. In addition, a 2-round expert-panel among 12 physicians was organized. Based on the expert-panel (in combination with published data), it was estimated that in Belgium rocuronium is used in about 58,100 surgical interventions per year. Reversal with sugammadex is performed in 21.5% of them. Mean age of the patients using sugammadex was 54 years (+/− 17 SD), 45% of the patients belonged to ASA (American Society of Anesthesiologists) category I-II (healthy-mild systemic disease), 33% to category>III, 84% had co-morbidities. Sugammadex is mainly used after gastroenterological surgery (53%; high contribution of bariatric-surgery), followed by gynaecological interventions (12%), estimates confirmed by the expert-panel. According to the experts, in 29% of the patients reversal with sugammadex was used outside the reimbursement conditions. The study confirms that, in Belgium, sugammadex is used when medically needed, a substantial part being used outside the reimbursement conditions.

Sugammadex Ideal Body Weight Dose Adjusted by Level of Neuromuscular Blockade in Laparoscopic Bariatric Surgery

Bariatric surgery patients are at risk of perioperative airway collapse. Neuromuscular blockade should be fully reversed before tracheal extubation. The optimal dosage of the reversal agent sugammadex in the morbidly obese is still unknown. This study explored the sugammadex dose adjusted according to train-of-four ratio (TOFR). Prospective observational study of consecutive patients scheduled for laparoscopic bariatric surgery. To reverse a deep blockade (2 or fewer posttetanic twitches), a dose of sugammadex of 4 mg/kg ideal body weight (IBW) was followed by a second dose of 2 mg/kg IBW if the TOFR was less than 0.9 after 3 min. To reverse a moderate blockade (reappearance of the second twitch in the TOF), a 2 mg/kg IBW dose of sugammadex was followed by a second dose of 2 mg/kg IBW if the TOFR was less than 0.9 after 2 min. Sugammadex effectiveness was reflected by the time required to obtain a TOFr of 0.9 or more. A total of 120 patients were included. The blockade was deep at the end of surgery in 43 and moderate in 77. The median times (range) to TOFR of 0.9 or more were 167 (20-460) seconds and 113 (28-300) seconds in deep and moderate blockades, respectively (P < 0.05). The percentage of patients requiring a second dose of sugammadex were larger after deep blockades (39.5% [n = 17] vs. 23.4% [n = 18] after moderate blockades); the difference was not significant. A sugammadex dose calculated according to IBW is insufficient for reversing both deep and moderate blockades in morbidly obese patients.

A randomised controlled trial comparing sugammadex and neostigmine at different depths of neuromuscular blockade in patients undergoing laparoscopic surgery*

Deep neuromuscular blockade during certain surgical procedures may improve operating conditions. Sugammadex can be used to reverse deep neuromuscular blockade without waiting for spontaneous recovery. This randomised study compared recovery times from neuromuscular blockade induced by rocuronium 0.6 mg.kg(-1), using sugammadex 4 mg.kg(-1) administered at 1-2 post-tetanic count (deep blockade) or neostigmine 50 μg.kg(-1) (plus atropine 10 μg.kg(-1)) administered at the re-appearance of the second twitch of a train-of-four stimulation (moderate blockade), in patients undergoing laparoscopic surgery. The primary efficacy variable was the time from the start of sugammadex/neostigmine administration to recovery of the train-of-four ratio to 0.9. Patients receiving sugammadex recovered 3.4 times faster than patients receiving neostigmine (geometric mean (95% CI) recovery times of 2.4 (2.1-2.7) and 8.4 (7.2-9.8) min, respectively, p<0.0001). Moreover, 94% (62/66) of sugammadex-treated patients recovered within 5 min, vs 20% (13/65) of neostigmine-treated patients, despite the difference in the depth of neuromuscular blockade at the time of administration of both drugs. The ability to provide deep neuromuscular blockade throughout the procedure but still permit reversal at the end of surgery may enable improved surgical access and an enhanced visual field.

Translocation of single‐stranded DNA through the α‐hemolysin protein nanopore in acidic solutions

The effect of acidic pH on the translocation of single-stranded DNA through the α-hemolysin pore is investigated. Two significantly different types of events, i.e. deep blockades and shallow blockades, are observed at low pH. The residence times of the shallow blockades are not significantly different from those of the DNA translocation events obtained at or near physiological pH, whereas the deep blockades have much larger residence times and blockage amplitudes. With a decrease in the pH of the electrolyte solution, the percentage of the deep blockades in the total events increases. Furthermore, the mean residence time of these long-lived events is dependent on the length of DNA, and also varies with the nucleotide base, suggesting that they are appropriate for use in DNA analysis. In addition to being used as an effective approach to affect DNA translocation in the nanopore, manipulation of the pH of the electrolyte solution provides a potential means to greatly enhance the sensitivity of nanopore stochastic sensing.

Sugammadex in antagonism of neuromuscular block in anesthesia: a clinical and economic profile

Sugammadex is a modified cyclodextrin which acts by encapsulating and inactivating the neuromuscular blocking agents (NMBAs) rocuronium and vecuronium, used to induce relaxation of skeletal muscles during surgery and to facilitate endotracheal intubation. The procedure of reversal of the block at the end of surgery can influence the time to discharge from the operating room and post-operative residual curarization (PORC) incidence, which is related to an increased rate of adverse respiratory events in the post-anaesthesia care unit. Cholinesterase inhibitors are frequently used to reverse neuromuscular block, but their use is associated with potential cardiovascular and respiratory side-effects. The recommended dose-range for sugammadex is 2-16 mg/kg, depending on the level of block: the dose is approximately 2 mg/kg for reversal of moderate blockade, 4 mg/kg for deep blockade and 16 mg/kg for the immediate reversal of a neuromuscular blockade as early as 3 minutes after 1-1.2 mg/kg of rocuronium. Four pivotal, phase III trials studied sugammadex in routine reversal of moderate, deep neuromuscular block and in the immediate reversal of rocuronium-induced block. In all the cases the drug demonstrated of being significantly more efficient than other reversal strategies, providing a faster reversal than the most used anticholinesterase comparator neostigmine. Sugammadex also appeared to have an acceptable safety profile. Acquisition cost of sugammadex is greater than that of neostigmine, but cost-savings related to the reduced theatre time and to the reduced incidence of PORC episodes can offset it. A Budget Impact analysis in the perspective of the hospital has been conducted for the Italian setting resulting in a total cost-save of 7,420 € for one year of activity. In conclusion, sugammadex appears to be a valuable innovation in anesthesiology. This drug represents a safe and effective alternative to anticholinesterase agents.

Reversión del bloqueo neuromuscular residual por atracurio y vecuronio con dosis bajas de neostigmina

To assess the effectiveness of low doses of neostigmine in the reversion of residual non-polarising neuromuscular blockade (RNMB). The work involved one hundred and nineteen adult patients, ASA I-III, anaesthetised with fentanyl, thiopental, O2-N2O-isoflurane and atracurium (n=62) or vecuronium (n=57). RNMB was monitored with continuous electromyography of adductor pollicis with TOF stimulation. When TOF-Ratio (TR) < 75%, neostigmine 0.035, 0.03, 0.025 or 0.02 mg/kg (and atropine 0.0175, 0.015, 0.0125 or 0.01 mg/kg) were administrated based on the degree of NMB (0-1, 2, 3 or 4) to TOF stimulation respectively, registering the time to achieve TR > 75% and secondary effects. Both groups were homogeneous. Twenty-five point eight percent (25.8%) (group A) and 21.1% (group V) presented TR>75% at the end of surgery, while 11.3% and 19.2% showed TR < 75% with 0-1 responses, 6.5% and 11.5% 2 responses, 4.8% and 7.6% 3 responses, and 51.6% and 50% 4 responses to TOF stimulation in groups A or V respectively. All patients who received neostigmine presented TR > 75% in 10.5+/-7 (group A) and 10.3+/-6.4 min. (group V). A predominance of secondary effects in the atracurium group was observed (p=0.027), basically due to excessive salivation, nausea and vomiting. There were no cases of RNMB. The reversion of the residual neuromuscular blockade of atracurium or vecuronium with low doses of neostigmine and atropine adjusted to the degree of RNMB is effective even in deep blockades, reducing the risk of secondary effects.

Muscle relaxants: a clinical update

The doses of neuromuscular blocking agents must be chosen in such a way as to allow enough spontaneous recovery to occur before the end of the procedure so that anticholinesterase-assisted recovery is possible. Stimulation of the facial nerve and assessment of the response of the corrugator supercilii is useful to predict intubating conditions and as a guide to deep blockade. However, the adequacy of recovery is best assessed by adductor pollicis monitoring.