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Understanding the Myths Surrounding Neuromuscular Blockade–reversal Agents

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Understanding the myths surrounding neuromuscular blockade–reversal agents

GE Healthcare’s Matti Laitinen, Global Product Manager for Neurology Parameters, and Mika Sarkela, a research and development engineer, recently participated in a discussion on agents designed to reverse neuromuscular blockade (NMB) and the importance of quantitative neuromuscular monitoring (NMT). Herein, their thoughts on the myths and challenges that surround NMT and the NMB reversal process are detailed.

Neuromuscular monitoring

Before and during surgery, neuromuscular-blocking agents (NMBAs) are used to facilitate intubation and ensure optimal conditions for surgery. However, patients who receive NMBAs can be at a risk for adverse postoperative effects of these agents. Residual paralysis is a major concern and can lead to respiratory complications including an increased risk of aspiration and pneumonia, hypoxemia, airway obstruction, the need for tracheal intubation, and increased length of stay in the postanesthesia care unit (PACU).1

During anesthesia administration, the anesthetist must continually assess a patient’s neuromuscular function. Typical clinical observations for such include the evaluation of grip strength and head lift; however, these techniques are unreliable and difficult to use in anesthesia-emergent patients. Separately, qualitative peripheral nerve stimulation assesses the response of the stimulated muscle. Unfortunately, this technique does not eliminate the risk of residual paralysis. As such, specialized quantitative monitors are available to supplement the aforementioned options. Those neuromuscular transmission (NMT) monitors provide automatic, numerical measurements indicating the muscle response to a stimulus and the associated level of neuromuscular block.

Research indicates, however, that the use of NMT monitoring devices is highly variable among anesthesia practitioners as well as between countries and institutions.2,3 In certain countries, such as Finland, NMT is considered the standard of care and is required whenever an NMBA is used. Conversely, in other regions or particular institutions, NMT is not considered mandatory and clinicians may instead rely only on clinical observation. “This is one of the biggest misconceptions,” said Laitinen, “and it is something we are working to change.”

According to Laitinen and Sarkela, there are various reasons for why practitioners or institutions may not require the use of NMT. Some issues relate to the monitoring devices themselves. For example, the setup and sensor placement required for measurement may be seen as complex and time-consuming. Certain devices may also be viewed as unreliable or prone to errors. Furthermore, components can be misplaced, as most NMT devices are handheld pieces of equipment that do not integrate into the monitoring system. Availability is a problem as well. “Even if there is [a] willingness to use the devices, they are simply not available at every institution,” said Laitinen.

Another important barrier to ubiquitous NMT use is the belief that it is possible to observe a patient’s NMB status by way of visual and tactile measures alone. “The [clinical] literature makes it clear that this is not true,” Laitinen stressed. “Still, many clinicians think it is possible to determine the level of NMB without quantitative monitoring.” Similarly, the connection between NMB and postoperative complications may not be sufficiently recognized. “Especially if an institution’s operating room is independent from the rest of the hospital, this linkage [between the lack of NMT and rates of residual paralysis] may not be clear,” Laitinen explained.

Another obstacle is the lack of official support for NMT use. Professional societies such as the European Society of Anaesthesiology and the American Society of Anesthesiologists have not delivered clear and strong recommendations calling for the mandatory use of NMT during anesthesia.

NMB reversal

At the conclusion of surgery, agents are frequently used to reverse NMB. The main classes of reversal agents are anticholinesterases (e.g., neostigmine) and cyclodextrins (e.g., sugammadex). The choice of reversal agent depends on many factors, including the NMBA in use, the profoundness of the blockade, the time available for reversal, and cost considerations.

The most commonly employed nondepolarizing NMB agents are rocuronium bromide and vecuronium bromide. Both neostigmine and sugammadex may be used to reverse blockage achieved with either of these NMB agents.  

Neostigmine

Neostigmine can reverse the effects of many commonly used NMBAs, including atracurium and cisatracurium. However, the time needed to achieve adequate reversal with this drug may vary significantly between patients. Moreover, neostigmine is efficient only when the NMB has spontaneously returned to one or two twitches on train-of-four (TOF) monitoring. Neostigmine will not reverse deep blockade.

Sugammadex

Sugammadex is effective only for reversing the effects of rocuronium or vecuronium, although it can be successful in reducing very deep blockade. “Many consider sugammadex a ‘miracle drug,’” said Laitinen. “It is very efficient, has few side effects, and does the job with all patient groups and in all levels of paralysis.” Because of these advantages, some may feel sugammadex does not require quantitative monitoring. However, too-early administration or a too-small dosage of sugammadex may lead to residual paralysis. In addition, depending on the geographic region, sugammadex may cost up to 20 times more than neostigmine, and many institutions have strict protocols for the use of this agent because of this high cost.

Regardless of the agent chosen to reverse NMB, none of these drugs preclude the need for quantitative NMT monitoring. “In fact, when both neostigmine and sugammadex are options, NMT may help [in deciding] between the two,” Laitinen suggested. NMT can also influence dosage size and timing of drug administration. For example, sugammadex is a very dose-dependent drug; the amount required to reverse a deep blockade may be four to eight times larger than that needed to mitigate a very light blockade. Underdosing increases the risk of residual paralysis. “It is very important to know how deep the blockade is in order to know how much sugammadex to administer,” Laitinen explained.

Measuring neuromuscular blockade 

The depth of NMB is routinely measured using electrodes and a small current to stimulate peripheral nerves, most commonly the ulnar nerve in the hand or the medial plantar nerve in the foot. Muscle response is automatically measured with a device. This so-called TOF monitoring assesses neuromuscular transmission based on the number of muscle responses detected. The TOF ratio is the ratio of the fourth muscle response to the first one and indicates NMB fade. Extubation after surgery is recommended only if the TOF ratio exceeds 0.9.1

Currently available NMT monitoring technology includes electromyography (EMG), which measures muscle fiber potentials; kinemyography (KMG), which measures thumb bending caused by the stimulusthum; and acceleromyography (AMG), which measures thumb acceleration.

In NMT monitoring, EMG is measured close to the site of the NMB action and directly measures electrical activity. Considered the gold standard, EMG measurement does not require any physical movement of the hand. “It works well even if the hand is not available at all or completely immobilized for the operation,” noted Sarkela, who emphasized that devices for measuring KMG and AMG in comparison have some limitations, adding that “[their] quality of the signal is not as good as EMG.” For example, a TOF ratio of 0.9 measured with an AMG-based NMT monitoring device may not indicate the achievement of adequate recovery for safe extubation. “There is [a] growing awareness of the superiority of the EMG signal,” Laitinen added.

The GE Healthcare solution for NMT monitoring 

At this time, GE Healthcare (Chicago, IL, USA) offers the only fully integrated NMT measurement module with the ability to measure both KMG- and EMG-based signals. The following three different NMT sensors provide maximal flexibility: the Mechanosensor (KMG), pediatric Mechanosensor (KMG), and Electrosensor (EMG).

Concluding remarks

Residual paralysis from anesthesia following surgery is a common problem despite the use of reversal agents. According to the literature, 20% to 40% of patients arrive in the PACU with signs of residual paralysis.4

Laitinen and Sarkela concur that this issue relates to the lack of quantitative NMT monitoring when reversal agents are applied. Prior surveys also concur, indicating that objective paralysis monitoring is performed in only 17% of patients.4

During the discussion, Laitinen commented that “the most proven and important benefits of NMT monitoring are to optimize NMBA dosage and, crucially, from a patient’s point of view, to be able to predict recovery and avoid residual paralysis.”

References

  1. Duţu M, Ivaşcu R, Tudorache O, et al. Neuromuscular monitoring: an update. Rom J Anaesth Intensive Care. 2018;25(1):55–60. DOI: 10.21454/rjaic.7518.251.nrm. Accessed July 4, 2019.
  2. Hammermeister KE, Bronsert M, Richman JS, Henderson WG. Residual neuromuscular blockade (NMB), reversal, and perioperative outcomes. Anesthesia Patient Safety Foundation (APSF) Newsletter. 2016;30(3):45–76. Accessed July 4, 2019
  3. Checketts MR, Alladi R, Ferguson K, et al. Recommendations for standards of monitoring during anaesthesia and recovery 2015: Association of Anaesthetists of Great Britain and Ireland. Anaesthesia. 2016;71(1):85–93. DOI: 10.1111/anae.13316. Accessed July 4, 2019
  4. Brull SJ, Kopman AF. Current status of neuromuscular reversal and monitoring: challenges and opportunities. Anesthesiology. 2017;126(1):173–190. DOI: 10.1097/ALN.0000000000001409. Accessed July 4, 2019.