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Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate tracheal intubation whilst being reversible with sugammadex. Together, this combination might offer full reversibility of a 'routine' or a 'rapid-sequence' induction anaesthesia. Whether this is useful, or even safe, requires careful evaluation., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: The isolated forearm technique is used to monitor intraoperative awareness. However, this technique cannot be applied to patients who must be kept deeply paralysed for >1h, because the tourniquet preventing the neuromuscular blocking agent from paralysing the forearm must be deflated from time to time. To overcome this problem, we tested the feasibility of a 'reversed' isolated forearm technique., Methods: Patients received rocuronium 0.6 mg kg(-1) i.v. to achieve muscle paralysis. A tourniquet was then inflated around one upper arm to prevent further blood supply to the forearm. Sugammadex was injected into a vein of this isolated forearm to antagonize muscle paralysis regionally. A dose titration of sugammadex to antagonize muscle paralysis in the isolated forearm was performed in 10 patients, and the effects of the selected dose were observed in 10 additional patients., Results: The sugammadex dose required to antagonize muscle paralysis in the isolated forearm was 0.03 mg kg(-1) in 30 ml of 0.9% saline. Muscle paralysis was antagonized in the isolated forearm within 3.2 min in nine of 10 patients; the rest of the patients' bodies remained paralysed. Releasing the tourniquet 15 min later did not affect the train-of-four count in the isolated forearm but significantly increased the train-of-four count in the other arm by 7%., Conclusions: Regional antagonization of rocuronium-induced muscle paralysis using a sugammadex dose of 0.03 mg kg(-1) injected into an isolated forearm was feasible and did not have relevant systemic effects., Clinical Trial Registration: The trial was registered at EudraCT (ref. no. 2013-002164-53) before patient enrolment began., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The aim of this dose-finding study was to evaluate the dose-response relationship of sugammadex and neostigmine to reverse a commonly observed level of incomplete recovery from rocuronium-induced neuromuscular block, that is, a train-of-four ratio (TOFR) ≥0.2., Methods: Ninety-nine anaesthetized patients received rocuronium 0.6 mg kg(-1) i.v. for tracheal intubation and, if necessary, incremental doses of 0.1-0.2 mg kg(-1). Neuromuscular monitoring was performed by calibrated electromyography. Once the TOFR recovered to 0.2, patients were randomized to receive sugammadex (0.25, 0.5, 0.75, 1.0, or 1.25 mg kg(-1) i.v.), neostigmine (10, 25, 40, 55, or 70 µg kg(-1) i.v.), or saline (n=9 per group). Primary and secondary end points were the doses necessary to restore neuromuscular function to a TOFR≥0.9 with an upper limit of 5 and 10 min for 95% of patients, respectively., Results: Neostigmine was not able to fulfil the end points. Based on the best-fitting model, the sugammadex dose estimation for recovery to a TOFR≥0.9 for 95% of patients within 5 and 10 min was 0.49 and 0.26 mg kg(-1), respectively., Conclusion: A residual neuromuscular block of a TOFR of 0.2 cannot be reversed reliably with neostigmine within 10 min. In the conditions studied, substantially lower doses of sugammadex than the approved dose of 2.0 mg kg(-1) may be sufficient to reverse residual rocuronium-induced neuromuscular block at a recovery of TOFR≥0.2., Clinical Trial Registration: NCT01006720., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: This study aimed to investigate whether reversal of rocuronium-induced neuromuscular blockade with sugammadex reduced the incidence of residual blockade and facilitated operating room discharge readiness., Methods: Adult patients undergoing abdominal surgery received rocuronium, followed by randomized allocation to sugammadex (2 or 4 mg kg(-1)) or usual care (neostigmine/glycopyrrolate, dosing per usual care practice) for reversal of neuromuscular blockade. Timing of reversal agent administration was based on the providers' clinical judgement. Primary endpoint was the presence of residual neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio <0.9, using TOF-Watch® SX. Key secondary endpoint was time between reversal agent administration and operating room discharge-readiness; analysed with analysis of covariance., Results: Of 154 patients randomized, 150 had a TOF value measured at PACU entry. Zero out of 74 sugammadex patients and 33 out of 76 (43.4%) usual care patients had TOF-Watch SX-assessed residual neuromuscular blockade at PACU admission (odds ratio 0.0, 95% CI [0-0.06], P<0.0001). Of these 33 usual care patients, 2 also had clinical evidence of partial paralysis. Time between reversal agent administration and operating room discharge-readiness was shorter for sugammadex vs usual care (14.7 vs. 18.6 min respectively; P=0.02)., Conclusions: After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU, and shortened the time from start of study medication administration to the time the patient was ready for discharge from the operating room., Clinical Trial Registration: Clinicaltrials.gov:NCT01479764., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] <30 ml min(-1)) vs those with normal renal function (CLCR ≥80 ml min(-1))., Methods: Sugammadex 4 mg kg(-1) was administered at 1-2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T4/T1) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within -1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed., Results: The intent-to-treat group comprised 67 patients (renal n=35; control n=32). Median (95% CI) time from sugammadex to recovery to T4/T1 ratio 0.9 was 3.1 (2.4-4.6) and 1.9 (1.6-2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6-2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg(-1)) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics., Conclusions: Sugammadex 4 mg kg(-1) provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex-rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population., Clinical Trial Registration: NCT00702715., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: A train-of-four ratio (TOFR) ≥0.9 measured by quantitative neuromuscular monitoring is accepted as an indication of sufficient neuromuscular recovery for extubation, even though many postsynaptic acetylcholine receptors may still be inhibited. We investigated whether antagonism with sugammadex after spontaneous recovery to TOFR≥0.9 further improves muscle function or subjective well-being., Methods: Following recovery to TOFR≥0.9 and emergence from anaesthesia, 300 patients randomly received either sugammadex 1.0 mg kg(-1) or placebo. Fine motor function (Purdue Pegboard Test) and maximal voluntary grip strength were measured before and after surgery (before and after test drug administration). At discharge from the postanaesthesia care unit, well-being was assessed with numerical analogue scales and the Quality-of-Recovery Score 40 (QoR-40)., Results: Patients' fine motor function [6 (sd 4) vs 15 (3) pegs (30 s)(-1), P<0.05] and maximal voluntary grip strength (284 (126) vs 386 (125) N, P<0.05) were significantly lower after anaesthesia compared with the pre-anaesthesia baseline. After sugammadex or placebo, motor function was significantly improved in both groups but did not reach the preoperative level. There was no difference between groups at any time. Global well-being was unaffected (QoR-40: placebo, 174 vs 185; sugammadex, 175 vs 186, P>0.05)., Conclusions: Antagonizing rocuronium at TOF≥0.9 with sugammadex 1.0 mg kg(-) (1) did not improve patients' motor function or well-being when compared with placebo. Our data support the view that TOFR≥0.9 measured by electromyography signifies sufficient recovery of neuromuscular function., Clinical Trial Registration: The trial is registered at ClinicalTrials.gov (NCT01101139)., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The routine use of neuromuscular blocking agents reduces the occurrence of unacceptable surgical conditions. In some surgeries, such as retroperitoneal laparoscopies, deep neuromuscular block (NMB) may further improve surgical conditions compared with moderate NMB. In this study, the effect of deep NMB on surgical conditions was assessed., Methods: Twenty-four patients undergoing elective laparoscopic surgery for prostatectomy or nephrectomy were randomized to receive moderate NMB (train-of-four 1-2) using the combination of atracurium/mivacurium, or deep NMB (post-tetanic count 1-2) using high-dose rocuronium. After surgery, NMB was antagonized with neostigmine (moderate NMB), or sugammadex (deep NMB). During all surgeries, one surgeon scored the quality of surgical conditions using a five-point surgical rating scale (SRS) ranging from 1 (extremely poor conditions) to 5 (optimal conditions). Video images were obtained and 12 anaesthetists rated a random selection of images., Results: Mean (standard deviation) SRS was 4.0 (0.4) during moderate and 4.7 (0.4) during deep NMB (P<0.001). Moderate block resulted in 18% of scores at the low end of the scale (Scores 1-3); deep block resulted in 99% of scores at the high end of the scale (Scores 4 and 5). Cardiorespiratory conditions were similar during and after surgery in both groups. Between anaesthetists and surgeon, there was poor agreement between scores of individual images (average κ statistic 0.05)., Conclusions: Application of the five-point SRS showed that deep NMB results in an improved quality of surgical conditions compared with moderate block in retroperitoneal laparoscopies, without compromise to the patients' peri- and postoperative cardiorespiratory conditions. Trial registration The study was registered at clinicaltrials.gov under number NCT01361149.

Neuromuscular blocking agents have been implicated in 60-70% of anaphylactic events associated with anaesthesia. We report two cases of probable hypersensitivity reaction to sugammadex and an additional suspected but less supported case of possible immune-mediated reaction or other adverse reaction. The patients were given a bolus of sugammadex 100 mg immediately before extubation. In all three patients, a possible allergic reaction was suspected within 4 min of sugammadex administration, but with different degrees of severity. Skin testing was positive in two of these patients. Hypersensitivity to sugammadex unaccompanied by cardiovascular or respiratory symptoms might be missed during the course of anaesthesia. Careful monitoring for possible allergic responses is required in patients who have received sugammadex.

A 78-yr-old woman presented for a panendoscopy to investigate dysphonia and dysphagia. Intubation was anticipated to be difficult but possible, and mask ventilation was anticipated to be possible. After induction of anaesthesia and after three attempts at intubation, a 'can't intubate, can ventilate' situation deteriorated to a 'can't intubate, can't ventilate' (CICV) situation. Rocuronium-induced neuromuscular block was successfully reversed with sugammadex, as evidenced by the restoration of diaphragmatic movement, the ability of the patient to move her limbs, and the presence of a train-of-four nerve stimulation with no fade; however, ventilation was still not possible. A cricothyroid puncture using a Ravussin needle was performed successfully to provide emergency oxygenation. A tracheostomy was performed to allow the panendoscopy. CICV situations are rare anaesthetic emergencies. While sugammadex can be relied upon to reverse rocuronium-induced neuromuscular block, it should not be relied upon to rescue all CICV events, especially where airway instrumentation has led to airway swelling. The availability of sugammadex does not obviate the need for emergency tracheal access in the event of failed oxygenation. The presence of head and neck pathology should lead to the consideration of securing the airway awake.

Background: Sugammadex is a modified γ-cyclodextrin with a novel mechanism of action for reversing the steroidal neuromuscular blocking agent rocuronium. Bispectral index (BIS) is an EEG-derived measure which can be sensitive to frontal electromyographic (EMG) artifacts. We compared BIS values before and after sugammadex or neostigmine neuromuscular block (NMB) reversal in patients with or without high EMG activity., Methods: During stable propofol/remifentanil anaesthesia and rocuronium-induced block, 48 patients were randomly allocated to receive sugammadex 4 mg kg(-1) or neostigmine 50 μg kg(-1)/glycopyrrolate 10 μg kg(-1), 10 min after the end of surgery., Results: Five minutes after sugammadex administration, mean BIS 50.1 (10.3) increased (P=0.018) to 61.7 (7.9) in 11 patients with high EMG activity. In contrast, BIS 49.3 (4.9) remained at 51.9 (5.4) in 13 patients who had no EMG activity. Fifteen minutes after neostigmine administration, mean BIS 51.9 (8.1) increased (P=0.007) to 63.9 (8.1) in 13 patients who had reappearance of muscle activity. However, in 11 patients who had no EMG activity, BIS 52.3 (7.4) remained at 53.3 (6.8). There was no significant difference between the sugammadex and neostigmine groups over time., Conclusions: We have shown that reversal of NMB with sugammadex or neostigmine increased BIS values dependent on the presence of EMG activity. Thus, the effect of muscle activity reappearance during rocuronium NMB reversal spuriously increasing the BIS value should be taken into consideration when relying on BIS monitoring for evaluating propofol/remifentanil recovery.

Background: Complete and fast recovery of neuromuscular function is very important in morbidly obese patients because of the possible influence of postoperative residual curarization (PORC) on respiratory function in the postoperative period. Recent reports underline incidences of the residual influence of neuromuscular blocking agents., Methods: Seventy morbidly obese (BMI >40 kg m(-2)) patients requiring general anaesthesia and receiving rocuronium for muscle relaxation were randomly assigned into two groups: at the end of the anaesthetic procedure, one group received sugammadex 2 mg kg(-1) of corrected body weight (Group SUG) and the other group received neostigmine 0.05 mg kg(-1) of CBW (Group NEO). At the end of surgery and when response reached a train-of-four (TOF) score of 2, patients received the study drugs. The neuromuscular function was recorded and time to achieve 90% of TOF (safe extubation) was measured. Patients were examined directly after arrival to the post-anaesthesia care unit (PACU) by a blinded investigator for the presence of PORC., Results: Thirty-five patients received sugammadex and 35 neostigmine. Mean dose of rocuronium was 87.9 vs 85.6 mg (P>0.05), mean time to 90% of TOF was 2.7 vs 9.6 min (P<0.05), and TOF at the PACU was 109.8% vs 85.5% (P<0.05) in Groups SUG and NEO, respectively., Conclusions: Administration of sugammadex provides fast recovery of neuromuscular function and prevents PORC in the morbidly obese, however neostigmine does not.

Background: This study compared the reversibility of rocuronium-induced profound neuromuscular block with sugammadex in younger and older patients., Methods: Fifteen younger (20-50 yr) and 15 older (≥70 yr) patients were sequentially enrolled in this study. After induction of anaesthesia and laryngeal mask insertion, contraction of the adductor pollicis muscle in response to ulnar nerve stimulation was quantified using acceleromyography during 1.0-1.5% end-tidal sevoflurane and remifentanil anaesthesia. All patients initially received rocuronium 1 mg kg(-1), followed by 0.02 mg kg(-1) when a post-tetanic count (PTC) of 1 or 2 was observed. After completion of surgery, at reappearance of 1-2 PTC, the time required for a single bolus dose of 4 mg kg(-1) sugammadex to produce recovery to a train-of-four (TOF) ratio of 0.9 was recorded., Results: There were no differences in the total dose of rocuronium administered between the younger [mean (sd): 93.4 (17.5) mg] and the older [97.5 (32.2) mg] groups. In all patients, adequate recovery of the TOF ratio to 0.9 was achieved after administration of sugammadex, although it was significantly slower in the older [3.6 (0.7) min, P<0.0001] than in the younger group [1.3 (0.3) min]. There were no clinical events attributable to recurarization., Conclusions: Sugammadex can adequately restore neuromuscular function in older patients, although a longer time is required to recover from profound rocuronium-induced neuromuscular block than in younger patients.

Sugammadex is a selective relaxant-binding agent, which reverses rocuronium-induced neuromuscular blocks of any depth by chemical encapsulation of rocuronium in the plasma in various groups of patients. We reported seven Caesarean section cases, undergoing general anaesthesia with thiopental (6 mg kg⁻¹) and rocuronium (0.6 mg kg⁻¹) who were given desflurane and fentanyl for maintenance of anaesthesia after delivery. The action of rocuronium may be prolonged in pregnant women. At the end of the operation, all patients had a significant degree of neuromuscular block. In five patients, there was no single twitch response and no TOF ratio, one patient had one twitch detectable, and in one patient, a TOF ratio of 3% was detected. The recommended dose of sugammadex for reversal of profound block (4 mg kg⁻¹) or moderate block (2 mg kg⁻¹) was given. In all patients, sugammadex provided rapid and sufficient reversal to TOF >0.9 within 2 min. All patients were monitored after operation, and no signs of recurarization occurred in any patient and no signs of neuromuscular weakness were observed.

Sugammadex 16 mg kg⁻¹ can be used for the immediate reversal of neuromuscular block 3 min after administration of rocuronium and could be used in place of succinylcholine for emergency intubation. We have systematically reviewed the efficacy and cost-effectiveness and made an economic assessment of sugammadex for immediate reversal. The economic assessment investigated whether sugammadex appears cost-effective under various assumptions about the value of any reduction in recovery time with sugammadex, the likelihood of a 'can't intubate, can't ventilate' (CICV) event, the age of the patient, and the length of the procedure. Three trials were included in the efficacy review. Sugammadex administered 3 or 5 min after rocuronium produced markedly faster recovery than placebo or spontaneous recovery from succinylcholine-induced block. No published economic evaluations were found. Our economic analyses showed that sugammadex appears more cost-effective, where the value of any reduction in recovery time is greater, where the reduction in mortality compared with succinylcholine is greater, and where the patient is younger, for lower probabilities of a CICV event and for long procedures which do not require profound block throughout. Because of the lack of evidence, the value of some parameters remains unknown, which makes it difficult to provide a definitive assessment of the cost-effectiveness of sugammadex in practice. The use of sugammadex in combination with high-dose rocuronium is efficacious. Further research is needed to clarify key parameters in the analysis and to allow a fuller economic assessment.

Background: Sugammadex shows a dose-response relationship for reversal of neuromuscular block (NMB) during propofol anaesthesia. Sevoflurane, unlike propofol, can prolong the effect of neuromuscular blocking agents (NMBAs), increasing recovery time. This open-label, randomized, dose-finding trial explored sugammadex dose-response relationships, safety, and pharmacokinetics when administered for reversal of moderate rocuronium- or vecuronium-induced NMB during sevoflurane maintenance anaesthesia., Methods: After anaesthesia induction with propofol, adult patients were randomized to receive single-dose rocuronium 0.9 mg kg⁻¹ or vecuronium 0.1 mg kg⁻¹, with maintenance doses as needed. Anaesthesia was maintained with sevoflurane. NMB was monitored using acceleromyography. After the last dose of NMBA, at reappearance of T(2), single-dose sugammadex 0.5, 1.0, 2.0, or 4.0 mg kg⁻¹ or placebo was administered. The primary efficacy variable was time from the start of sugammadex administration to recovery of T₄/T₁ ratio to 0.9. Safety assessments were performed throughout., Results: The per-protocol population comprised 93 patients (rocuronium, n=46; vecuronium, n=47). A statistically significant dose-response relationship was demonstrated for mean recovery times of T₄/T₁ ratio to 0.9 with increasing sugammadex dose with both NMBAs: rocuronium, 96.3 min (placebo) to 1.5 min (sugammadex 4.0 mg kg⁻¹); vecuronium, 79.0 min (placebo) to 3.0 min (sugammadex 4.0 mg kg⁻¹). Plasma sugammadex concentrations indicated linear pharmacokinetics, independent of NMBA administered. No study drug-related serious adverse events occurred. Evidence of reoccurrence of block was reported in seven patients [sugammadex 0.5 mg kg⁻¹ (suboptimal dose), n=6; 2.0 mg kg⁻¹, n=1]., Conclusions: During sevoflurane maintenance anaesthesia, sugammadex provides well-tolerated, effective, dose-dependent reversal of moderate rocuronium- and vecuronium-induced NMB.

Background: Re-intubation and re-operation may occasionally be required after neuromuscular block (NMB) reversal. This study evaluated block onset times of a second dose of rocuronium (1.2 mg kg(-1)) after sugammadex reversal of rocuronium 0.6 mg kg(-1)., Methods: In this open-label study of healthy anaesthetized volunteers, subjects received rocuronium 0.6 mg kg(-1), were antagonized at 1-2 post-tetanic counts with sugammadex 4.0 mg kg(-1), and received rocuronium 1.2 mg kg(-1) at 5, 7.5, 10, 15, 20, 22.5, 25, 27.5, 30, 45, or 60 min after sugammadex. Spontaneous recovery occurred after repeat rocuronium dose. Primary endpoints were the onset time of maximal block (time to lowest T(1) value reached) and the clinical duration of block (until T(1)=25%) after repeat rocuronium dose., Results: Sixteen subjects were included. For subjects receiving rocuronium 1.2 mg kg(-1) 5 min after sugammadex (n=6), mean (sd) onset time (to T(1)=0) was 3.06 (0.97) min; range, 1.92-4.72 min. For repeat dose time points ≥25 min (n=5), mean onset was faster (1.73 min) than for repeat doses <25 min (3.09 min) after sugammadex. The duration of block ranged from 17.7 min (rocuronium 5 min after sugammadex) to 46 min (repeat dose at 45 min). Mean duration was 24.8 min for repeat dosing <25 min vs 38.2 min for repeat doses ≥25 min., Conclusions: Rapid re-onset of NMB occurred after repeat dose of rocuronium 1.2 mg kg(-1) as early as 5 min after sugammadex in healthy volunteers. Re-onset of block took longer if second rocuronium dose was <25 min after sugammadex. The duration of action of second rocuronium dose increased with later repeat dose time points.

Background: This clinical study evaluated the speed of reversal of profound rocuronium block in ponies using sugammadex and investigated the differences in onset and recovery from block in three different muscle groups., Methods: Anaesthesia was induced and maintained with isoflurane in oxygen 100% in eight ponies. Neuromuscular monitoring was performed at each site using acceleromyography: in the extensor muscles of the pelvic limb (peroneal nerve) and thoracic limb (radial nerve), and in the orbicularis oris muscle (OOM; facial nerve). Rocuronium 0.6 mg kg(-1) i.v. was administered, followed 5 min later by sugammadex 4 mg kg(-1) i.v. Onset time (onsetROC), maximum block, and time to recovery of the train-of-four ratio to 0.9 (TOFR=0.9) were recorded. The differences between monitored sites were compared using one-way anova followed by a post hoc Dunn's test., Results: Onset of ROC was significantly delayed in OOM compared with both limbs [pelvic limb, thoracic limb, and OOM: 43.1 (sd 16.9), 50.6 (15.9), and 204.4 (35.8) s, respectively; P<0.001]. Complete block was achieved in the pelvic and thoracic limbs, but in none of the eight ponies in the OOM [mean T1=15.3 (9.4)%; range: 7-36%]. No differences were observed between muscle sites in recovery to TOFR=0.9 [pelvic limb, thoracic limb, and OOM: 2.3 (0.9), 3.4 (1.7), and 2.8 (2.1) min, respectively]. No adverse effects of sugammadex were detected throughout the study period., Conclusions: Sugammadex can be used to reverse profound rocuronium-induced block in ponies during isoflurane anaesthesia. Thoracic limb muscles represent a suitable alternative for monitoring neuromuscular block compared with pelvic limb muscles.

Background: Sugammadex, a modified gamma-cyclodextrin, is the first selective relaxant binding agent that specifically encapsulates the steroidal neuromuscular blocking agent, rocuronium. The action of rocuronium is prolonged in patients with renal failure. As sugammadex is primarily cleared renally, this phase III trial investigated the efficacy and safety of sugammadex for reversal of rocuronium-induced neuromuscular block (NMB) in patients with end-stage renal failure., Methods: Thirty adult patients were studied: 15 renally impaired [creatinine clearance (CL(CR)) <30 ml min(-1)] and 15 controls (CL(CR)>80 ml min(-1)). Anaesthesia was induced and maintained using i.v. opiates and propofol. Neuromuscular monitoring was performed by acceleromyography and train-of-four (TOF) nerve stimulation. Rocuronium (0.6 mg kg(-1)) was given, followed by a single i.v. dose of sugammadex (2.0 mg kg(-1)) at reappearance of the second twitch of the TOF. The primary efficacy variable was time from administration of sugammadex to recovery of the TOF ratio to 0.9. Safety variables included clinical evidence of reoccurrence of NMB., Results: After sugammadex administration, the mean (sd) time to recovery of the TOF ratio to 0.9 was 2.0 (0.72) min in renal patients and 1.65 (0.63) min in controls (NS). Recurrence of NMB was not observed in any patient. No sugammadex-related serious adverse events were reported., Conclusions: Sugammadex administered at reappearance of T(2) rapidly and effectively reverses NMB induced by rocuronium in renal failure and healthy patients. Sugammadex was well tolerated by all patients. Further safety studies on sugammadex in patients with severe renal impairment are warranted.

Background: Cholinesterase inhibitor-based reversal agents, given in the absence of neuromuscular block, evoke a partial upper airway obstruction by decreasing skeletal upper airway muscle function. Sugammadex reverses neuromuscular block by encapsulating rocuronium. However, its effects on upper airway integrity and breathing are unknown., Methods: Fifty-one adult male rats were anaesthetized with isoflurane, tracheostomized, and a femoral artery and vein were cannulated. First, we compared the efficacy of sugammadex 15 mg kg(-1) and neostigmine 0.06 mg kg(-1) to reverse respiratory effects of rocuronium-induced partial paralysis [train-of-four ratio (T4/T1)=0.5]. Subsequently, we compared the safety of sugammadex and neostigmine given after recovery of the T4/T1 to 1, by measuring phasic genioglossus activity and breathing., Results: During partial paralysis (T4/T1=0.5), time to recovery of minute volume to baseline values was 10.9 (2), 75.8 (18), and 153 (54) s with sugammadex, neostigmine, and placebo, respectively (sugammadex was significantly faster than neostigmine and placebo, P<0.05). Recovery of T4/T1 was also faster for sugammadex than neostigmine and placebo. Neostigmine administration after complete recovery of T4/T1 decreased upper airway dilator muscle activity to 64 (30)% of baseline and decreased tidal volume (P<0.05 for both variables), whereas sugammadex had no effect on either variable., Conclusions: In contrast to neostigmine, which significantly impairs upper airway dilator muscle activity when given after recovery from neuromuscular block, a reversal dose of sugammadex given under the same conditions does not affect genioglossus muscle activity and normal breathing. Human studies will be required to evaluate the clinical relevance of our findings.

Background: Reversal of the residual effect of rocuronium or cisatracurium by neostigmine may be slow and associated with side-effects. This randomized, safety-assessor-blinded study compared the efficacy of sugammadex, a selective relaxant binding agent for reversal of rocuronium-induced neuromuscular block, with that of neostigmine for reversal of cisatracurium-induced neuromuscular block. The safety of sugammadex and neostigmine was also evaluated., Methods: Adult surgical patients (ASA class I-III) were randomized to sugammadex 2.0 mg kg(-1) for reversal of block induced by rocuronium 0.6 mg kg(-1), or neostigmine 50 microg kg(-1) for reversal of block induced by cisatracurium 0.15 mg kg(-1). Anaesthesia was induced and maintained using i.v. propofol and remifentanil, fentanyl, or sufentanil. Neuromuscular function was monitored using acceleromyography (TOF-Watch SX). Sugammadex or neostigmine was administered at reappearance of T(2). The primary efficacy variable was time for recovery of the train-of-four (TOF) ratio to 0.9., Results: Eighty-four patients were randomized, 73 of whom received sugammadex (n=34) or neostigmine (n=39). Time from start of administration of reversal agent to recovery of the TOF ratio to 0.9 was 4.7 times faster with sugammadex than with neostigmine (geometric mean=1.9 vs 9.0 min, P<0.0001). Reversal of block was sustained in all patients. There were no serious adverse effects from either reversal agent and no significant changes in any measure of safety, except for similar elevations in urinary N-acetyl glucosaminidase in both groups., Conclusions: Sugammadex 2.0 mg kg(-1) administered at reappearance of T(2) was significantly faster in reversing rocuronium-induced blockade than neostigmine was in reversing cisatracurium-induced block.

Background: Sugammadex rapidly reverses rocuronium- and vecuronium-induced neuromuscular block. To investigate the effect of combination of sugammadex and rocuronium or vecuronium on QT interval, it would be preferable to avoid the interference of anaesthesia. Therefore, this pilot study was performed to investigate the safety, tolerability, and plasma pharmacokinetics of single i.v. doses of sugammadex administered simultaneously with rocuronium or vecuronium to anaesthetized and non-anaesthetized healthy volunteers., Methods: In this phase I study, 12 subjects were anaesthetized with propofol/remifentanil and received sugammadex 16, 20, or 32 mg kg(-1) combined with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1); four subjects were not anaesthetized and received sugammadex 32 mg kg(-1) with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1) (n=2 per treatment). Neuromuscular function was assessed by TOF-Watch SX monitoring in anaesthetized subjects and by clinical tests in non-anaesthetized volunteers. Sugammadex, rocuronium, and vecuronium plasma concentrations were measured at several time points., Results: No serious adverse events (AEs) were reported. Fourteen subjects reported 23 AEs after study drug administration. Episodes of mild headache, tiredness, cold feeling (application site), dry mouth, oral discomfort, nausea, increased aspartate aminotransferase and gamma-glutamyltransferase levels, and moderate injection site irritation were considered as possibly related to the study drug. The ECG and vital signs showed no clinically relevant changes. Rocuronium/vecuronium plasma concentrations declined faster than those of sugammadex., Conclusions: Single-dose administration of sugammadex 16, 20, or 32 mg kg(-1) in combination with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1) was well tolerated with no clinical evidence of residual neuromuscular block, confirming that these combinations can safely be administered simultaneously to non-anaesthetized subjects. Rocuronium and vecuronium plasma concentrations decreased faster than those of sugammadex, reducing the theoretical risk of neuromuscular block developing over time.

Sugammadex is the first selective relaxant binding agent and reverses rocuronium-induced neuromuscular block. A case is reported in which a patient accidentally received a high dose of sugammadex (40 mg kg-1) to reverse a rocuronium-induced (1.2 mg kg-1) profound neuromuscular block. A fast and efficient recovery from profound neuromuscular block was achieved and no adverse events or other safety concerns were reported.

Background: Reversal of neuromuscular block can be accomplished by chemical encapsulation of rocuronium by sugammadex (Org 25969), a synthetic gamma-cyclodextrin derivative. The present study determined the time course of the reversal action of sugammadex on rocuronium-induced block in the anaesthetized Rhesus monkey using train-of-four stimulation., Methods: A bolus injection of rocuronium 100 microg kg(-1) (about 1xED(90)) was given to determine the degree of neuromuscular block reached by this dose. After complete spontaneous recovery, a rapid bolus injection of sugammadex, 1 mg kg(-1), was given and at different time intervals (15, 30 or 60 min, in three different experiments) the effect of another rocuronium bolus injection of 100 microg kg(-1) was determined., Results: Injection of the first dose of rocuronium resulted in a mean neuromuscular block (depression of first twitch) of 93 (SEM=1.6)%. Fifteen minutes after injection of sugammadex the same rocuronium dose resulted in 17% (SEM=5.6) block. After 30 and 60 min these maximum blocks amounted to 49% (SEM=7.6) and 79% (SEM=4.2), respectively. The estimated half-life of sugammadex in Rhesus monkey is 30 (SEM=4.9) min., Conclusions: The half-life of sugammadex (Org 25969), a new fast and efficient reversal agent for rocuronium-induced block, is relatively short in the Rhesus monkey, implying the possibility to perform neuromuscular block by rocuronium shortly after reversal of a prior block. In translation to the human situation differences in rocuronium sensitivity and kinetics should be taken into account.

Background: Binding of the steroidal molecule of rocuronium by a cyclodextrin is a new concept for reversal of neuromuscular block. The present study evaluated the ability of Sugammadex Org 25969, a synthetic gamma-cyclodextrin derivative, to reverse constant neuromuscular block of about 90% induced by rocuronium or the non-steroidal neuromuscular blocking drugs, mivacurium or atracurium, in the anaesthetized Rhesus monkey., Methods: After a bolus injection of rocuronium, mivacurium or atracurium, a continuous infusion of these drugs was started to maintain the first twitch contraction of the train-of-four at approximately 10% of its baseline value. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either sugammadex 0.5 or 1.0 mg kg(-1) was given in the rocuronium-induced blockade and sugammadex 1.0 mg kg(-1) was given in the mivacurium- and atracurium-induced blockade., Results: Sugammadex caused a rapid and complete reversal of rocuronium-induced neuromuscular block. The recovery time to train of four ratio=0.9 after spontaneous recovery was 14.4 min (sd=3.4 min; n=14). This was reduced significantly (P<0.001) to 3.7 min (sd=3.3 min; n=4) with sugammadex 0.5 mg kg(-1) and to 1.9 min (sd=1.0 min; n=4) with sugammadex 1.0 mg kg(-1). Signs of residual blockade or re-curarization were not observed. Reversal of mivacurium- or atracurium-induced neuromuscular block (n=2 in each experiment) by sugammadex (1.0 mg kg(-1)) was not effective. In all experiments, injection of sugammadex had no effects on blood pressure or heart rate., Conclusions: Sugammadex is effective in reversing rocuronium, but not mivacurium- or atracurium-induced neuromuscular block.

Background: At present, reversal of neuromuscular block induced by steroidal neuromuscular blocking agents (NMBAs) is achieved by administration of cholinesterase inhibitors. Chemical encapsulation of steroidal NMBAs, such as rocuronium, by a cyclodextrin is a new concept in neuromuscular block reversal. The present study evaluates the capacity of nine synthetic cyclodextrin derivatives (Org 25288, Org 25289, Org 25467, Org 25168, Org 25169, Org 25555, Org 25166, Org 26142, and Org 25969) to reverse constant neuromuscular block of approximately 90%, induced by rocuronium infusion in the Rhesus monkey, using single twitch stimulation. The ability of these cyclodextrin derivatives to reverse neuromuscular block was compared with the reversal of the same neuromuscular block by the commonly used combination of neostigmine and atropine., Methods: After a bolus injection of rocuronium, continuous infusion was started to reduce twitch contractions to approximately 10% of baseline values. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either one of the nine cyclodextrin derivatives or a combination of neostigmine and atropine was given., Results: Recovery with cyclodextrin derivatives Org 26142 and Org 25969 was faster than after a combination of neostigmine and atropine (P<0.05). Injection of these cyclodextrin derivatives did not affect blood pressure or heart rate. Signs of residual block or recurarization were not observed in any of these experiments. In the experiments in which a combination of neostigmine and atropine was given, two animals showed signs of abdominal discomfort as frequently seen after the administration of neostigmine and significant changes in circulatory variables., Conclusions: Chemical encapsulation or chelation of rocuronium is a new concept in reversing neuromuscular block induced by rocuronium.

Background: Org 25969 is a cyclodextrin compound designed to reverse a rocuronium-induced neuromuscular block. The aim of this study was to explore the efficacy, dose-response relation and safety of Org 25969 for reversal of a prolonged rocuronium-induced neuromuscular block., Methods: Thirty anaesthetized adult patients received rocuronium 0.6 mg kg(-1) as an initial dose followed by increments to maintain a deep block at a level of <10 PTCs (post-tetanic counts) recorded every 6 min. Neuromuscular monitoring was carried out using accelerometry, in a train-of-four (TOF) mode using TOF-WatchSX. At recovery of T2, following at least 2 h of neuromuscular block, patients received their randomly assigned dose of 0.5, 1.0, 2.0, 4.0 or 6.0 mg kg(-1) of Org 25969. Anaesthesia and neuromuscular monitoring were continued for a minimum period of 30 min after Org 25969 administration. The main end-point of the study was the time to achieve a sustained recovery of TOF ratio to 0.9. Patients were followed up for 7 days after anaesthesia., Results: The results showed a dose-related decrease in the average time taken to attain a TOF ratio of 0.9 from 6:49 (min:s) with the 0.5 mg kg(-1) dose to 1:22 with the 4.0 mg kg(-1) dose. Weighted non-linear regression analysis showed the fastest achievable time to TOF ratio of 0.9 to be 1:35. Org 25969 produced no major adverse effects., Conclusion: Org 25969 effectively reversed a deep and prolonged neuromuscular block induced by rocuronium. The effective reversal dose appears to be 2-4 mg kg(-1).

Dose-response relationships for the antagonism of intermediate-acting neuromuscular blocking agents have not been evaluated previously in children. We have examined the dose-response relationships for neostigmine antagonism of 90% rocuronium-induced neuromuscular block in children and adults, during nitrous oxide-1 MAC of isoflurane anaesthesia. We studied 40 children, aged 2-10 yr, and 50 adults, aged 18-60 yr; all received a single bolus dose of rocuronium 0.6 mg kg-1 and accelerometry was used to monitor neuromuscular transmission. When the first twitch of the train-of-four (TOF) response (T1) recovered to 10% of its control (T0), one of five doses of neostigmine 0, 5, 10, 20 or 50 micrograms kg-1 was given by random allocation to each of the study groups (n = 8 children and n = 10 adults). Recovery of T1 and TOF ratio (T4/T1%) was recorded for 10 min after initial administration of neostigmine. Onset time of rocuronium-induced block was faster in children than in adults (mean 64.6 (95% confidence intervals 57.7-71.5) s vs 83.7 (70.7-96.6) s; P < 0.05). The time to 10% recovery of T1/T0 was shorter in children than in adults (25.4 (22.9-27.9) min vs 38.8 (36.1-41.4) min; P < 0.001). Spontaneous and antagonist-assisted recovery were more rapid in children than in adults. Adequate recovery (T4/T1 of 80%) occurred in children at 4, 5 and 8 min after neostigmine 50, 20 and 10 micrograms kg-1, respectively. Adequate recovery was not produced in adults by any dose of neostigmine within 10 min. The effective doses of neostigmine required to achieve a TOF ratio of 80% (ED80) after 10 min in children and adults were, respectively, 7.10 (5.2-9.8) micrograms kg-1 and 56.56 (45.5-71.9) micrograms kg-1 (P < 0.001). There was no advantage in administering doses of neostigmine greater than 20 micrograms kg-1 to antagonize 90% rocuronium-induced neuromuscular block in children. In contrast, it appeared prudent to use neostigmine 50 micrograms kg-1 or more for adequate antagonism of a similar degree of block in adults.

To test if recovery of neuromuscular transmission is complete after the use of neostigmine under standardized conditions, we have measured adductor pollicis mechanical activity in response to 0.1 Hz (twitch height), train-of-four (TOF) and 100 Hz (RF 100 Hz) ulnar nerve stimulations. We studied 56 adult anaesthetized (thiopentone, fentanyl, nitrous oxide in oxygen) patients, allocated randomly to one of four groups (n = 14) to receive rocuronium (group Roc), vecuronium (group Vec), atracurium (group Atr) or pancuronium (group Pan). Recovery of neuromuscular transmission was studied for 15 min after neostigmine 40 micrograms kg-1 was given at 25% recovery of twitch height. Fifteen minutes after antagonism, the TOF ratio was 0.91 (SEM 0.01), 0.88 (0.02) and 0.92 (0.01) (ns), and RF 100 Hz was 0.78 (0.01), 0.79 (0.02) and 0.78 (0.01) (ns) respectively, in patients in groups Roc, Vec and Atr, respectively. In patients in group Pan, TOF ratio and RF 100 Hz were only 0.76 (0.01) and 0.33 (0.04) respectively (P < 0.01, one-way analysis of variance, Duncan's multiple classification range tests). In contrast with pancuronium, antagonism of rocuronium-, vecuronium- and atracurium-induced neuromuscular blocks produced a similar high degree of recovery of neuromuscular transmission.