[Update on muscle relaxation : What comes after succinylcholine, rocuronium and sugammadex?] / Update Muskelrelaxation : Was kommt nach Succinylcholin, Rocuronium und Sugammadex?

Due to the great advantages, it is not possible to imagine current practice in anesthesia without the adminstration of muscle relaxants. For a long time the administration of succinylcholine for rapid sequence induction (RSI) was considered to be the state of the art for patients at risk for aspiration. The favorable characteristics are, however, accompanied by many, sometimes severe side effects. Due to the development of non-depolarizing muscle relaxants, in particular rocuronium in combination with sugammadex, there is the possibility to achieve a profile of action similar to succinylcholine with low side effects. After the introduction of sugammadex onto the market, further substances were conceived, which enable a complete encapsulation of muscle relaxants. Calabadion is a very promising new substance for the antagonization of muscle relaxants, which can antagonize the action of steroid as well as benzylisoquinoline types. In the USA new muscle relaxants are currently being tested, which have a rapid onset and the effect can be reversed by L­cysteine. One of the most promising substances is gantacurium, which is currently being tested in the USA in phase III trials. It remains to be seen whether these muscle relaxants, which are not yet on the market and drugs for reversal of neuromuscular blockade have the potential to become a real alternative to the combination of rocuronium and sugammadex.

Electroconvulsive Therapy Considerations for Transgendered Patients.

As the transgender patient population continues to grow, health care providers will need to become aware of elements unique to the transgender community in order to provide the highest quality of care. Neuromuscular blockade with succinylcholine is routinely administered to patients undergoing electroconvulsive therapy (ECT). Decreased amounts or activity of pseudocholinesterase in serum can lead to prolonged duration of muscle paralysis. Causes of reduced action by pseudocholinesterase include genetically abnormal enzymes, reduced hepatic production, pregnancy, and various drug interactions. Estrogen supplementation taken by transitioning patients may affect the duration of neuromuscular blockade.This is a case of a 32-year-old male-to-female transgender patient with prolonged apnea following ECT treatment for severe, refractory depression. Further investigation revealed the patient was on estrogen therapy as a part of her transition and laboratory testing demonstrated reduced serum pseudocholinesterase activity. Further laboratory testing demonstrated reduced serum pseudocholinesterase activity. Succinylcholine dosing was titrated to an appropriate level to avoid prolonged apnea in subsequent ECT treatments. Physicians and other health care providers are faced with a unique population in the transgender community and must be aware of distinctive circumstances when providing care to this group. Of specific interest, many transitioning and transitioned patients can be on chronic estrogen supplementation. Neuromuscular blockade in those patients require attention from the anesthesiology care team as estrogen compounds may decrease pseudocholinesterase levels and lead to prolonged muscle paralysis from succinylcholine.

Efficacy of sugammadex for the reversal of moderate and deep rocuronium-induced neuromuscular block in patients pretreated with intravenous magnesium: a randomized controlled trial.

BACKGROUND: Magnesium enhances the effect of rocuronium. Sugammadex reverses rocuronium-induced neuromuscular block. The authors investigated whether magnesium decreased the efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular block. METHODS: Thirty-two male patients were randomized in a double-blinded manner to receive magnesium sulfate (MgSO4) 60 mg/kg or placebo intravenously before induction of anesthesia with propofol, sufentanil, and rocuronium 0.6 mg/kg. Neuromuscular transmission was monitored using TOF-Watch SX acceleromyography (Organon Ltd., Dublin, Ireland). In 16 patients, sugammadex 2 mg/kg was administered intravenously at reappearance of the second twitch of the train-of-four (moderate block). In 16 further patients, sugammadex 4 mg/kg was administered intravenously at posttetanic count 1 to 2 (deep block). Primary endpoint was recovery time from injection of sugammadex to normalized train-of-four ratio 0.9. Secondary endpoint was recovery time to final T1. RESULTS: Average time for reversal of moderate block was 1.69 min (SD, 0.81) in patients pretreated with MgSO4 and 1.76 min (1.13) in those pretreated with placebo (P = 0.897). Average time for reversal of deep block was 1.77 min (0.83) in patients pretreated with MgSO4 and 1.98 min (0.58) in those pretreated with placebo (P = 0.572). Times to final T1 were longer compared with times to normalized train-of-four ratio 0.9, without any difference between patients pretreated with MgSO4 or placebo. CONCLUSION: Pretreatment with a single intravenous dose of MgSO4 60 mg/kg does not decrease the efficacy of recommended doses of sugammadex for the reversal of a moderate and deep neuromuscular block induced by an intubation dose of rocuronium.

Recovery time after sugammadex reversal of rocuronium-induced muscle relaxation for electroconvulsive therapy is independent of cardiac output in both young and elderly patients.

PURPOSE: This study was conducted to (1) compare the recovery times from rocuronium-induced muscle relaxation after reversal with sugammadex between young and elderly patients undergoing electroconvulsive therapy (ECT), and (2) to examine the existence of a correlation between cardiac index and reversibility of rocuronium-induced neuromuscular block with sugammadex after ECT. METHODS: Seventeen patients (young group, 50 years or younger, n = 8; elderly group, 70 years or older, n = 9) who were scheduled to undergo ECT were studied. Anesthesia was induced using propofol (1.0 mg/kg) followed by rocuronium (0.6 mg/kg). Assisted mask ventilation was initiated with 100% oxygen. Cardiac index was monitored noninvasively throughout the procedure. After the first twitch of the train of four (TOF) was assessed as being zero by neuromuscular monitoring, an electroshock stimulus was applied bilaterally. Immediately after the seizure stopped, patients were given 8-mg/kg sugammadex intravenously to reverse the muscle relaxation. Neuromuscular monitoring was continued until recovery of the TOF ratio to 0.9 at the tibial nerve in the leg. The time to recovery of the TOF to 0.1 and 0.9 was compared in both groups. RESULTS: Although no significant difference in return to a TOF of 0.1 was found between the groups, there were significant differences in both recovery to a TOF of 0.9 and the time interval to the first spontaneous breath between groups (time to recovery to a TOF of 0.9, young group, 403 ± 37 seconds; elderly group, 443 ± 36 seconds; P < 0.05). In contrast, there was no relationship between cardiac index after ECT and recovery time to TOF of 0.9. CONCLUSIONS: Although recovery time to TOF of 0.9 after the administration of 8.0-mg/kg sugammadex was longer in the elderly patients than in the young patients, it had no relationship with cardiac output after ECT.

[Effective reversal of muscle relaxation by rocuronium using sugammadex in a patient with myasthenia gravis undergoing laparoscopic cholecystectomy].

As myasthenia gravis affects neuromuscular transmission, these patients show various responses to neuromuscular blocking drugs. We report a successful use of the sugammadex in a myasthenic patient to reverse rocuronium-induced neuromuscular block. A 69-year-old woman was scheduled for laparoscopic cholecystectomy and total of rocuronium 20 mg was administered. After spontaneous recovery of T1, we administered sugammadex 200mg intravenously, reversing neuromuscular blockade to a train-of-four ratio (T4/T1) of 100% within 30 sec. Sugammadex can be used to reverse rocuronium-induced neuromuscular blockade in patients with myasthenia gravis, thereby avoiding the need for reversal with acetylcholinesterase inhibitors.

[Case-Report: Reversal of a deep neuromuscular block with sugammadex after rapid sequence induction with high-dose rocuronium bromide]. / Kasuistik: Rapid Sequence Induction - Reversion einer tiefen neuromuskulären Blockade durch Sugammadex.

Sugammadex can reverse rocuronium-induced muscular relaxation by encapsulation of steroidal muscle relaxants without muscarinergic side effects. Clinical studies show effective dose-dependent reversal of neuromuscular blockades after rocuronium and vecuronium. We report on a patient with deep neuromuscular block at the end of surgery following rapid sequence induction of anesthesia with high-dose rocuronium, who could rapidly be reversed without side effects after adequate i.v. sugammadex application.

[Pharmacology of sugammadex]. / Pharmacologie du sugammadex.

Sugammadex is a new molecule derived from a known pharmacological class : the cyclodextrins known and used in human for many years. It was recently demonstrated that cyclodextrins could encapsulate and bind strongly steroidal neuromuscular blocking agents. Among cyclodextrins gamma-cyclodextrins proved to be more efficient. The binding of cyclodextrins to rocuronium and compound's water solubility was greatly improved by addition of 8 side chains to glycopyranoses units and the presence of a negative charge to the end of these side-chains. Animal studies have clearly demonstrated that sugammadex is faster in onset than anticholinesterase agents and is specific of steroidal neuromuscular blocking agents. It cannot reverse neuromuscular block induced by succinylcholine or benzylisoquinolines such as atracurium or cisatracurium. In human, the dose of sugammadex required to reverse shallow block is 2 mg/kg approximately whereas 4 mg/kg is needed to reverse deep level of neuromuscular block with a few responses at the post tetanic count at the adductor pollicis. The use of sugammadex was not associated with recurrence of block when an adequate dose was administered.

An update on sugammadex sodium.

Sugammadex sodium is the generic drug name for the novel modified gamma cyclodextrin that terminates neuromuscular blockade induced by aminosteroidal neuromuscular blocking agents. Published phase II and phase III clinical data support preclinical and clinical phase I study findings of fast, safe, and efficacious reversal of all levels of neuromuscular blockade induced by rocuronium and vecuronium. Low levels of neuromuscular blockade induced by pancuronium have also been successfully reversed by sugammadex. This agent does not reverse the bis-isoquinoline neuromuscular blocking agents. Special patient populations, including pediatric, elderly, cardiac, and renal-compromised subjects, have been studied in phase III. This update focuses on the most recent findings of phase II and III clinical studies.

Infusion requirements and reversibility of rocuronium at the corrugator supercilii and adductor pollicis muscles.

BACKGROUND: The aim of this study is to compare the infusion rates required to maintain a constant neuromuscular block and the reversibility of rocuronium at the corrugator supercilii muscle (CSM) and the adductor pollicis muscle (APM). METHODS: We randomly allocated 30 female patients into two groups of 15 patients each to monitor neuromuscular block at either the CSM or the APM. After induction of anaesthesia and laryngeal mask insertion, contraction of the CSM to the facial nerve stimulation or that of the APM to the ulnar nerve stimulation was quantified using an acceleromyograph during 1.0-1.5% end-tidal sevoflurane anaesthesia. All the patients received a bolus of 1 mg/kg rocuronium. When the first twitch (T1) of train-of-four (TOF) recovered to 10% of the control, rocuronium infusion was commenced and maintained at T1 of 10% of the control at the CSM or APM for 120 min. Immediately after rocuronium infusion was discontinued, the time required for 0.04 mg/kg neostigmine-facilitated recovery to a TOF ratio of 0.9 was recorded. RESULTS: Rocuronium infusion dose after a lapse of 120 min was significantly larger in the CSM than in the APM [7.1 (2.3) vs. 4.7 (2.6) microg/kg/min; P=0.001]. The time for facilitated recovery was shorter in the CSM than in the APM [11.4 (3.8) vs. 16.2 (6.0) min; P=0.016]. CONCLUSION: A larger rocuronium infusion dose was required to maintain a constant neuromuscular block at the CSM. Neostigmine-mediated reversal was faster at the CSM.

Preclinical pharmacology of sugammadex.

Since the introduction of nondepolarizing neuromuscular blocking agents, acetylcholinesterase inhibitors have been used to increase the speed of recovery from neuromuscular blockade. The major disadvantages of acetylcholinesterase inhibitors are their lack of activity against profound neuromuscular blockade and their activity outside the neuromuscular junction resulting in unwanted side effects, requiring cotreatment with a muscarinic antagonist. An alternative to acetylcholinesterase inhibitors is the encapsulating agent sugammadex. This agent has been specifically designed to encapsulate the steroidal neuromuscular blocking agents rocuronium and vecuronium. This review describes the effects of sugammadex in in vitro tissue and in vivo animal experiments. The encapsulation approach allows reversal of any degree of neuromuscular blockade because the dose of sugammadex can be adjusted to encapsulate sufficient neuromuscular blocking molecules to cause effective reversal. Because this interaction is a drug-drug interaction, reversal can be achieved very fast but is limited by the circulation time. Sugammadex is also effective against neuromuscular blockade under conditions with reduced acetylcholine release, which potentiate the action of neuromuscular blocking agents. Sugammadex does not cause cholinergic side effects, preventing the need of coadministration of muscarinic antagonists. Because of these properties, sugammadex has the potential to become a very useful drug for the management of neuromuscular blockade.

Reversal of rocuronium-induced neuromuscular blockade by pyridostigmine in patients with Duchenne muscular dystrophy.

BACKGROUND: The aim of this study was to investigate the effect and safety of pyridostigmine for the reversal of a neuromuscular block (NMB) in patients with Duchenne muscular dystrophy (DMD). In patients with DMD recovery from a rocuronium-induced NMB is markedly delayed. METHODS: Fourteen DMD patients (aged between 11 and 19 years) scheduled for elective scoliosis repair were studied. Following tracheal intubation without muscle relaxant, all patients received a single dose of rocuronium 0.6 mg.kg(-1). NMB was monitored by acceleromyography at the adductor pollicis muscle. When the first twitch height (T1) of the train-of-four (TOF) had recovered to 25% seven patients received either pyridostigmine 0.1 mg.kg(-1) (the anticholinergic drug with a long duration of action) or saline in a blinded manner. The times to attain TOF ratio of 0.9 were recorded. For comparison the Mann-Whitney U-test was used. RESULTS: Recovery to TOF ratio of 0.9 was significantly (P < 0.05) accelerated by pyridostigmine [84 (median), 57-141(range)] compared with controls (148, 84-243 min). The recovery time (time between T1 of 25% and TOF of 90%) was also significantly (P < 0.01) shortened by pyridostigmine (15, 8-49 vs 76, 43-144 min, respectively). Time to recovery of T(1) to 90% was not different between the groups (108, 63-134 vs 169. 61-208 min, respectively). CONCLUSIONS: Pyridostigmine 0.1 mg.kg(-1) effectively reversed a rocuronium-induced NMB in DMD patients.

Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study.

BACKGROUND: Reversal of rocuronium-induced neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a modified gamma-cyclodextrin derivative. This study investigated the efficacy and safety of sugammadex in reversing rocuronium-induced profound neuromuscular blockade at 5 min in American Society of Anesthesiologists physical status I and II patients. METHODS: Forty-five American Society of Anesthesiologists physical status I and II patients (aged 18-64 yr) scheduled to undergo surgical procedures (anticipated anesthesia duration >/= 90 min) were randomly assigned to a phase II, multicenter, assessor-blinded, placebo-controlled, parallel, dose-finding study. Anesthesia was induced and maintained with propofol and an opioid. Profound neuromuscular blockade was induced with 1.2 mg/kg rocuronium bromide. Sugammadex (2.0, 4.0, 8.0, 12.0, or 16.0 mg/kg) or placebo (0.9% saline) was then administered 5 min after the administration of rocuronium. Neuromuscular function was monitored by acceleromyography, using train-of-four nerve stimulation. Recovery time was the time from the start of administration of sugammadex or placebo, to recovery of the train-of-four ratio to 0.9. Safety assessments were performed on the day of the operation and during the postoperative and follow-up period. RESULTS: A total of 43 patients received either sugammadex or placebo. Increasing doses of sugammadex reduced the mean recovery time from 122 min (spontaneous recovery) to less than 2 min in a dose-dependent manner. Signs of recurrence of blockade were not observed. No serious adverse events related to sugammadex were reported. Two adverse events possibly related to sugammadex were reported in two patients (diarrhea and light anesthesia); however, both patients recovered without sequelae. CONCLUSIONS: Sugammadex rapidly and effectively reversed profound rocuronium-induced neuromuscular blockade in humans and was well tolerated.

Time course of action of sugammadex (Org 25969) on rocuronium-induced block in the Rhesus monkey, using a simple model of equilibration of complex formation.

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.

Chemical encapsulation of rocuronium by synthetic cyclodextrin derivatives: reversal of neuromuscular block in anaesthetized Rhesus monkeys.

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.

First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide.

BACKGROUND: Acetylcholinesterase inhibitors are widely used for the reversal of neuromuscular blocking agents. However, acetylcholinesterase inhibitors have several side effects and are not effective during profound block. Org 25969 is a modified gamma-cyclodextrin that encapsulates the neuromuscular blocking agent, rocuronium bromide (Esmeron/Zemuron, NV Organon, Oss, The Netherlands), forming a tightly bound complex with an association constant of approximately 10 m. Chemical encapsulation of rocuronium promotes dissociation of rocuronium from the acetylcholine receptor, thereby reversing the neuromuscular block without the side effects associated with acetylcholinesterase inhibitors. METHODS: Twenty-nine healthy male volunteers were enrolled to investigate the safety, pharmacokinetics, and efficacy of Org 25969. In part 1, Org 25969 or placebo was administered to 19 subjects during one to three treatment periods each. In part 2, a further 10 subjects received general anesthesia on two separate occasions, using an intubating dose of 0.6 mg/kg rocuronium. Three minutes after rocuronium administration, Org 25969 or placebo was given in random order. Six doses of 0.1-8.0 mg/kg Org 25969 were evaluated. Neuromuscular block was measured using an acceleromyograph, the TOF-Watch-SX (NV Organon, Oss, The Netherlands). RESULTS: All adverse events related to Org 25969 treatment were of limited duration and mild intensity, except for a period of paresthesia, seen in one patient receiving 8 mg/kg Org 25969, which was of moderate intensity. No adverse events required any treatment, and all subjects recovered from them. When 8 mg/kg Org 25969 was given, the train-of-four ratio returned to 0.9 within 2 min after its administration. No signs of recurarization were observed. CONCLUSIONS: Org 25969 was both well tolerated and effective in reversing neuromuscular block induced by rocuronium in 29 human volunteers.