Neuromuscular Blocking Agents

Neuromuscular blocking agents (NMBA) are potent muscle relaxants, which are also known as muscle relaxers or neuromuscular blockers, are a type of medication which reduced function of skeletal muscle function.

Neuromuscular blocking agents are routinely used during the administration of anesthesia to allow surgical access to body cavities, in particular the abdomen and thorax, without hindrance from voluntary or reflex muscle movement. The introduction of these agents in 1942 marked a major advance in anesthesia and surgery, allowing the anesthesiologist to maintain respiratory function during prolonged and complex surgery.Neuromuscular blocking drugs are also used in the care of critically ill patients undergoing intensive therapy, to facilitate compliance with mechanical ventilation when sedation and analgesia alone have proved inadequate.

The widespread use of neuromuscular blocking agents (NMBA) was a significant milestone in the development of anesthesia.

Popular neuromuscular blocking agents are: Rocuronium, vecuronium, succinylcholine and cisatracurium.

For more information please refer to:

1. J M Hunter. New neuromuscular blocking drugs. N Engl J Med.1995;332(25):1691-9.

2. T A Torda. The neuromuscular blocking drugs. Med J Aust. 1988;149(6):316-9.
Trends in the Use of Neuromuscular Blocking Agents

Since 1943, neuromuscular blocking agents (NMBAs) have been established as muscle relaxants in the practice of anaesthesia and surgery to improve the safety of anaesthesia and later to facilitate intubation, mechanical ventilation, and surgical conditions. Currently, increasing evidence indicates that high-dose NMBAs improve surgical conditions, especially in laparoscopic surgery. Despite advances in technology, pharmacology, and quality assurance, residual neuromuscular blockade (rNMB) remains a persistent problem.

In 1979, residual neuromuscular blockade was defined as a train-of-four ratio (TOFR) < 0.7 in the post-anaesthesia care unit (PACU) . Increasing insight into residual neuromuscular blockade resulted in higher thresholds, from a TOFR > 0.8 in 1996 to a TOFR > 0.9 in 2000. In 2003, clinically relevant signs of residual neuromuscular blockade were found up to a TOFR of 1.0. Residual neuromuscular blockade is iatrogenic and preventable and is associated with an increased risk of postoperative airway obstruction, pulmonary complications, and unplanned ICU admission.

A study performed in 211 hospitals in Europe showed that any neuromuscular transmission monitoring is used in only 42.1% of patients receiving a neuromuscular blocking agent. Increasing the rate of neuromuscular transmission monitoring in clinical practice has proven to be a formidable challenge.

There were no clear changes in neuromuscular blocking agent types or dosage between 2015 and 2019, but there was a trend towards more active reversal with a more precise dose of sugammadex. In patients with a presumed higher a priori risk of pulmonary complications, reversal with sugammadex is more frequently used. In addition, the use of higher doses of rocuronium (e.g. deep neuromuscular blockade or emergency surgery) is associated with the use of sugammadex. The implementation of neuromuscular transmission monitoring with automatic recording may have contributed to a reduction in the number of patients extubated in the operating room, with spontaneous recovery, without documented neuromuscular transmission measurements, or with an inadequate TOFR at extubation.

Newly published guidelines from both the EU and the US recommended quantitative neuromuscular monitoring at the adductor pollicis muscle.

For more information please refer to:

1. Bowman WC. Neuromuscular block. Br J Pharmacol. 2006;147(Suppl 1):S277-86

2. Bruintjes MH, van Helden EV, Braat AE, Dahan A, Schefer GJ, van Laarhoven CJ, et al. Deep neuromuscular block to optimize surgical space conditions during laparoscopic surgery: a systematic review and meta-analysis. Br J Anaesth. 2017;118(6):834-42.

3. Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Engbaek J, Skovgaard LT, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand. 1997;41(9):1095-103.

4. Blobner M, Hunter JM, Meistelman C, Hoeft A, Hollmann MW, Kirmeier E, et al. Use of a train-of-four ratio of 0.95 versus 0.9 for tracheal extubation: an exploratory analysis of POPULAR data. Br J Anaesth. 2020;124(1):63-72.

5. Cammu G. Residual Neuromuscular Blockade and Postoperative Pulmonary  Complications: What Does the Recent Evidence Demonstrate? Curr Anesthesiol Rep. 2020:1-6.

6. Eikermann M, Vogt FM, Herbstreit F, Vahid-Dastgerdi M, Zenge MO, Ochterbeck C, et al. The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Am J Respir Crit Care Med. 2007;175(1):9-15.

7. Eikermann M, Groeben H, Hüsing J, Peters J. Accelerometry of adductor pollicis  muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology. 2003;98(6):1333-7.

8. Kirmeier E, Eriksson LI, Lewald H, Jonsson Fagerlund M, Hoeft A, Hollmann M, et al. Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study. Lancet Respir Med. 2019;7(2):129-40.

9. Xará D, Santos A, Abelha F. Adverse respiratory events in a post-anesthesia care unit. Arch Bronconeumol. 2015;51(2):69-75.

10. Viby-Mogensen J, Jørgensen BC, Ording H. Residual curarization in the recovery room. Anesthesiology. 1979;50(6):539-41.

11. Viby-Mogensen J, Engbaek J, Eriksson LI, Gramstad L, Jensen E, Jensen FS, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand. 1996;40(1):59-74.

12. Viby-Mogensen J. Postoperative residual curarization and evidence-based anaesthesia. Br J Anaesth. 2000;84(3):301-3.

13. Piet Krijtenburg, Arjen de Boer, Lori D. Bash. Trends in the use of neuromuscular blocking agents, reversal agents and neuromuscular transmission monitoring: a single-centre retrospective cohort study. Krijtenburg et al. Perioperative Medicine (2024) 13:22.

14. Thomas Fuchs-Buder, Carolina S. Romero. Peri-operative management of neuromuscular blockade: A guideline from the European Society of Anaesthesiology and Intensive Care. Eur J Anaesthesiol 2023; 40:82-94

Side Effects of Neuromuscular Blocking Agents

Neuromuscular blocking agents are often used to optimize mechanical ventilation, facilitate endotracheal intubation, stop overt shivering during therapeutic hypothermia following cardiac arrest, and may have a role in the management of life-threatening conditions. However, adverse effects such as venous thrombosis, patient awareness during paralysis, development of critical illness myopathy, autonomic interactions, and residual paralysis following cessation of NMBA use are still concerned about by anesthesiologists and doctors.

Moreover, muscle relaxants are one of the main causes of perioperative anaphylaxis. The mortality rate is estimated at 4%, despite adequate resuscitation. These reactions usually appear just after induction of anesthesia and involve skin, respiratory, and cardiovascular signs.

Clinically wide used reversal agents such as neostigmine, pyridostigmine, and edrophonium, are inhibitors of acetylcholinesterase (AChE), which leads to nonselective activation of muscarinic acetylcholine receptors (mAChR), thus causing many side-effects, for example, bradycardia, hypotension, increased salivation, nausea, vomiting, abdominal cramps, diarrhoea, and bronchoconstriction. In clinical pratice, these drugs are usually used in combination with a mAChR antagonist such as atropine or glycopyrrolate, which themselves also have a number of side-effects, such as dry mouth, blurred vision and tachycardia.
Residual Neuromuscular Block in Perioperative Period

Residual neuromuscular block is the unwanted presence of signs and symptoms of muscle weakness in the perioperative period and outside of the operation room after the administration of neuromuscular blocking agents and is defined by a combination of quantitative and qualitative measures. A train-of-four ratio (TOFR) recorded on a quantitative neuromuscular monitor was used to quantify RNMB. The TOFR represents four supramaximal stimuli delivered every 0.5 s (2 Hz) and the muscle response to the fourth stimulus is compared to the first stimulus. A ratio of the fourth to the first response of TOF (train of four) less than 0.90 (90%) defines the residual neuromuscular block. Although the definition of residual neuromuscular block has changed over time due to clinical observations of weakness at lower TOFRs, the TOFR<0.9 is currently the most accurate quantitative definition of residual neuromuscular block.

A quantitative TOFR < 0.9 has been associated with various unwanted symptoms of weakness that include an inability to breathe normally and maintain a patent airway,swallow dysfunction, lack of a strong cough, and even an inability to smile or talk. These undesirable outcomes maybe prevented if anesthesia professionals ensure the return of TOFR ≥ 0.9 in the perioperative space. As a result, the widely recommended and accepted TOFR associated with higher rates of full clinical recovery from neuromuscular block is ≥0.9 measured at the adductor pollicis.

Studies have suggested that postoperative pulmonary complications such as pneumonia, respiratory failure, atelectasis, and upper airway obstruction result in increased postoperative mortality are associated with residual neuromuscular block. And residual neuromuscular block has been further associated with prolonged lengths of stay in the post anesthesia care unit and decreased patient satisfaction. Residual neuromuscular block remains a significant issue in perioperative care and is frequently unrecognized, despite more perioperative provider acknowledgment that residual neuromuscular block continues to affect patient perioperative outcomes and the incidence of residual neuromuscular block remains unacceptably high.

2. Harlan, S.S.; Philpott, C.D.; Foertsch, M.J.; Takieddine, S.C.; Harger Dykes, N.J. Sugammadex Efficacy and Dosing for Rocuronium Reversal Outside of Perioperative Settings. Hosp. Pharm. 2023, 58, 194–199.

3. Murphy, G.S.; Brull, S.J. Residual neuromuscular block: Lessons unlearned. Part I: Definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth. Analg. 2010, 111, 120–128

4. Hile, G.B.; Ostinowsky, M.E.; Sandusky, N.P.; Howington, G.T. Evaluation of Sugammadex Dosing for Neurological Examination in the Emergency Department. J. Pharm. Pract. 2023.

5. Ali, H.H.; Utting, J.E.; Gray, C. Stimulus frequency in the detection of neuromuscular block in humans. Br. J. Anaesth. 1970, 42, 967–978.

6. Naguib, M.; Kopman, A.F.; Lien, C.A.; Hunter, J.M.; Lopez, A.; Brull, S.J. A survey of current management of neuromuscular block in the United States and Europe. Anesth. Analg. 2010, 111, 110–119

7. Thilen, S.R.; Weigel, W.A.; Todd, M.M.; Dutton, R.P.; Lien, C.A.; Grant, S.A.; Szokol, J.W.; Eriksson, L.I.; Yaster, M.; Grant, M.D.; et al. 2023 American Society of Anesthesiologists Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade: A Report by the American Society of Anesthesiologists Task Force on Neuromuscular Blockade. Anesthesiology 2023, 138, 13–41.

Incidence of Residual Neuromuscular Block After Reversal with Sugammadex in the Absence of Monitoring

A study conducted in two 5-month periods preceded and followed the introduction of sugammadex into clinical practice in five university-affiliated teaching hospitals in Japan demonstrated that the risk of TOFR0.9 after tracheal extubation after sugammadex remains a high as 9.4% in a clinical setting in which neuromuscular monitoring was not used.

In the study, neostigmine was used to antagonize rocuronium-induced neuromuscular blockade in the first phase, and sugammadex was used in the second phase. The timing and doses of rocuronium, neostigmine, and sugammadex were determined by the attending anesthesiologists without the use of neuromuscular function monitoring devices. To ascertain the incidence of postoperative residual neuromuscular weakness, the train-of-four ratio (TOFR) was determined acceleromyographically after tracheal extubation.

The incidence (95% confidence interval) of TOFR <0.9 under spontaneous recovery, after neostigmine, and after sugammadex, was 13.0% (2.8%–33.6%), 23.9% (16.2%–33.0%), and 4.3% (1.7%–9.4%), respectively. The incidence (95% confidence interval) of TOFR <1.0 in these groups was 69.6% (47.1%–86.6%), 67.0% (57.3%–75.7%), and 46.2% (36.9%–55.6%), respectively.

For more detail information, please refer to:

1. Yoshifumi Kotake, Ryoichi Ochiai, Takahiro Suzuki, Reversal with Sugammadex in the Absence of Monitoring Did Not Preclude Residual Neuromuscular Block, Anesth Analg 2013;117:345–51, DOI: 10.1213/ANE.0b013e3182999672

The Development History of Sugammadex

Shortly after the launch of rocuronium in 1994, questions arose about a possible action of rocuronium on smooth muscle neurotransmission. Dr. Bom, an expert in smooth muscle studies, was invited to collaborate on this subject. He first attempted to dissolve rocuronium in organic solvents that were traditionally used for smooth muscle studies, none of which were able to solubilize rocuronium. Next, he decided to examine cyclodextrins, which were demonstrated to dissolve steroidal hormones in earlier studies. Cyclodextrins are rigid, ring-shaped molecules composed of sugar units. The outside of the cyclodextrin is hydrophilic, which makes the molecule water-soluble. The hole in the middle of the cyclodextrin ring is hydrophobic, which allows lipophilic molecules, like steroids, to enter this cavity, creating water-soluble complexes.

Since rocuronium has a steroidal nucleus, Dr .Bom speculated that rocuronium would form complexes with cyclodextrins. This binding would prevent rocuronium from acting on the nicotinic acetylcholine receptor and allow rapid reversal of neuromuscular blockade. His initial studies confirmed that rocuronium formed complexes with cyclodextrins. However, this binding was weak, allowing rocuronium to easily disassociate. Several modifications of the molecule were required to increase affinity. The cavity of the cyclodextrin was too small, so the cavity had to be extended by the addition of side-chains to each sugar unit. To ensure that the side-chains did not enter the cavity, negatively charged end-groups had to be attached to the side-chains. These modifications would allow a tight complex to form between the quaternary nitrogen of the rocuronium and the negatively charged ends of the side-chains. Dr. Mingqiang Zhang, a medical chemist, then provided a long list of commercially available cyclodextrin molecules. The pharmacologists created in-vitro and in-vivo screening models, which allowed the creation of new cyclodextrin derivatives.

In March of 1999, the first batch of Org 25969 (sugammadex) was produced. In all pharmacological screening tests, this molecule showed the desired profile. The first human study was performed in healthy volunteers and published in 2005. This investigation demonstrated that 3 minutes after the administration of a normal intubation dose of rocuronium (0.6 mg/kg), 8 mg/kg of sugammadex could completely reverse neuromuscular blockade.

Sugammadex was first be approved in European Union in 2008. In 2007, new drug application was submitted to FDA of Unites States. However, the FDA issued Complete Response Letter for three times in next 8 years, and finally approve the NDA application in on December 16, 2015. Sugammadex is approved in 57 countries now.

Since the product was approved for marketing, The sales of sugammadex sodium injection have risen year by year, and according to the financial report of Merck, its global sales in 2022 reached $1.865 billion.

However, sugammadex was developed to selectively bind to rocuronium, it has much lower affinity with other steroidal muscle relaxants, such as vecuronium and pancuronium, and has no affinity with other classes of muscle relaxants (i.e. succinylcholine and the benzylisoquinoliums (mivacurium, atracurium and cisatracurium).

For more information, please refer to:

1. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005;103: 695–703.

2. Schaller SF, Fink H. Sugammadex as a reversal agent for neuromuscular block: an evidence-based review. Core Evidence 2013:8 57–67.

3. Glenn Murphy, MD. The Development and Regulatory History of Sugammadex in the United States. Circulation. 2016 30(3).

Sugammadex was Recommended Over Neostigmine by the ASA and the ESA

American Society of Anesthesiologists published an updated version of guidelines for monitoring and antagonism of neuromuscular blockade on 6 January 2023.

The notable updated recommendations include:

1. We recommend quantitative monitoring over qualitative assessment to avoid residual neuromuscular blockade. (Strong)

2. We recommend sugammadex over neostigmine at deep, moderate, and shallow depths of neuromuscular blockade induced by rocuronium or vecuronium, to avoid residual neuromuscular blockade.*(Strong)

3. We suggest neostigmine as a reasonable alternative to sugammadex at minimal depth of neuromuscular blockade. (Strong)

The European Society of Anaesthesiology and Intensive Care recommended using sugammadex to antagonise deep, moderate and shallow neuromuscular blockade induced by aminosteroidal agents in a guideline for peri-operative management of neuromuscular blockade published on Feb 1, 2023.

For more information, please refer to:

What adverse reactions patients might have after administration of Bridion

The label of Bridion demonstrates that adverse reactions reported in ≥10% of patients at a 2, 4, or 16 mg/kg Bridion dose with a rate higher than the placebo rate are: vomiting, pain, nausea, hypotension, and headache.

A total of 16,219,410 adverse events were analyzed in VigiBase between January 1, 2010 and December 31, 2019, and 2,032 were associated with sugammadex. The frequent reactions were recurrence of neuromuscular blockade (n = 54, IC 6.74, IC025 6.33), laryngospasm (n = 53, IC 6.05, IC025 5.64), bronchospasm (n = 119, IC 5.63, IC025 5.36) and bradycardia (n = 169, IC 5.13, IC025 4.90). Among 3,717 ADR in 2,032 patients, 53 were fatal, the most frequent fatal ADR was death (9/53).

For more information, please refer to:

1. Qiang Lyu, Pei Ye, Hewei Zhang, Safety of sugammadex for reversal of neuromuscular block: A postmarketing study based on the World Health Organization pharmacovigilance database. Br. J. Clin. Pharmacol. 2022 May 24. doi: 10.1111/bcp.15417.

Severe Perioperative Anaphylaxis Due to Allergy to the Sugammadex-Rocuronium Complex

There are several reports revealing that the sugammadex-rocuronium complex may cause perioperative anaphylaxis, sometimes anaphylactic shock may happen.

It is advised to perform skin-tests not only with sugammadex and rocuronium separately, but also with a mixture of both of them, when skin-test results are negative for the separated drugs. The case reports demonstrated that it is possible to be nonallergic to both sugammadex and rocuronium but allergic to the inclusion complex of the 2 drugs. Failure to test with this host–guest complex in the investigation of an anaphylactic event during anesthesia in which sugammadex has been used may leadto inability to correctly diagnose the cause.

Anesthesiologists and healthcare providers should be aware of the possibility of anaphylaxis from the sugammadex-rocuronium complex, as well as from sugammadex or rocuronium alone.

For more detail information, please refer to:

Postoperative Recurarization after Reversal of Rocuronium with Sugammadex

Recurarization is defined as an increase in neuromuscular block after a variable period of recovery and was reported in the past with the use of acetylcholinesterase inhibitors, but is increasingly being reported with sugammadex, where muscle strength appears to recover more reliably.

Recurarization may occur with the onset of respiratory acidosis, administration of magnesium or aminoglycoside antibiotics, or other factors that decrease the safety factors in the presence of low concentrations of muscle relaxants. Some rocuronium molecules remain unbound in the central compartment in some patients who receive an insufficient dose of sugammadex. These free molecules may redistribute to the peripheral compartment, migrate to the neuromuscular junction, and cause further muscle relaxation.

There are several recurarization cases reported after reversal of rocuronium with sugammadex, 1 case in an obese patient, 1 case in a patient with prolonged rocuronium infusion, 4 cases in pediatric patients.

The perioperative neuromuscular monitoring could reduce the risk of recurarization.

For more information please refer to:

1. Amanda N. Lorinc, Katheryne C. Lawson, Jonathan A. Niconchuk, Katharina B. Modes, John D. Moore, and Bruce R. Brenn, Residual Weakness and Recurarization After Sugammadex Administration in Pediatric Patients: A Case Series. International Anesthesia Research Society.

DOI: 10.1213/XAA.0000000000001225

3. Tetsuya Murata, Toshi Kubodera, Masakazu Ohbayashi, Kichiro Murase, Yushi U. Adachi, Naoyuki Matsuda. Recurarization after sugammadex following a prolonged rocuronium infusion for induced hypothermia. Can J Anesth/J Can Anesth (2013) 60:508–509.

DOI: 10.1007/s12630-013-9909-7

4. Fre´de´rique Le Corre, Salmi Nejmeddine, Che´rif Fatahine, Claude Tayar,  Jean Marty, Benoıˆt Plaud, Recurarization after sugammadex reversal in an obese patient. Can J Anesth/J Can Anesth (2011) 58:944–947.

DOI: 10.1007/s12630-011-9554-y

Bridion was a significant milestone in the development of anesthesia.