Monitoring and Antagonism of Neuromuscular Blockade

- RECOMMENDATIONS

This Guideline deals with the basic elements of the Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade.

The Guidelines Development Group (GDG) of the Egyptian Board of Anesthetics, Surgical Intensive Care, and Pain Management has adopted with modification:

2023 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. Thilen S R, Weigel W A, Todd MM, et al. January Anesthesiology 138(1):p 13-41, January 2023. | DOI: 10.1097/ALN.0000000000004379 (Reference No. 1) Supported by the American Society of Anesthesiologists and developed under the direction of the Committee on Practice Parameters, Karen B. Domino, M.D., M.P.H. (Chair).

Neuromuscular Monitoring: Patient Outcomes

1.     When neuromuscular blocking drugs are administered, we recommend against clinical assessment alone to avoid residual neuromuscular blockade, due to the insensitivity of the assessment. (Strong, Moderate evidence)

2.     We recommend quantitative monitoring over qualitative assessment to avoid residual neuromuscular blockade. (Strong, Moderate evidence)

	Neuromuscular Monitoring: Patient Outcomes
Strength	Strong
Benefit of Direction	Beneficial. Quantitative monitoring guarantees full reversal of paralysis.
Evidence	Moderate strength of evidence. ASA Task Force 2023 RCTs, observational, prospective and retrospective cohort studies*. Large multinational prospective cohort study, single-institution study, 2 RCTs, single trial and prospective cohort study **
Remarks	The clinical definition of adequate recovery of neuromuscular function may vary when the results of monitoring with acceleromyography are not normalized, and the train-of-four ratio may recover to values greater than 1.0. Normalization of train-of-four ratios to the baseline (control) value obtained before neuromuscular block is accomplished by dividing the postoperative measurements by the baseline value.

*The ASA Task Force panel 2023 [1] identified randomized controlled trials (RCTs) [4,5] and observational studies [6,7] that reported lower incidences of residual neuromuscular blockade with quantitative monitoring compared with qualitative assessment or clinical assessment. A prospective study [6] and a retrospective cohort study [7] included comparisons of quantitative monitoring with clinical assessment alone; a before–after design [8] compared quantitative monitoring with peripheral nerve stimulator or clinical assessment—all defined residual neuromuscular blockade as a train-of-four ratio less than 0.9 assessed in the PACU.

**A large multinational prospective cohort study [9] did not detect a difference in a composite pulmonary complication outcome (respiratory failure, hypoxia, pulmonary infection or infiltrates, atelectasis, aspiration pneumonia, bronchospasm, or pulmonary edema) in patients with quantitative versus qualitative assessment (very low strength of evidence for pulmonary complications). A single-institution before–after quality improvement study reported fewer pulmonary complications using quantitative monitoring compared with qualitative assessment [10]. Two RCTs [5,11] reported the incidence of hypoxia (two of the three reported a lower incidence with quantitative monitoring‚ one no events; low strength of evidence). A single trial [5] reported episodes of bronchospasm (1 event, 72 participants), and a prospective cohort study [12] reported pneumonia (2 events, 155 participants; both very low strength of evidence). Events were uncommon, and a quantitative evidence synthesis was not performed. It should be noted that there is not one universally accepted definition of postoperative pulmonary complications.

Neuromuscular Monitoring: Confirmation of Train-of-four Ratio Greater than or Equal to 0.9 before Extubation

3.     When using quantitative monitoring, we recommend confirming a train-of-four ratio greater than or equal to 0.9 before extubation. (Strong, Moderate evidence)

	Neuromuscular Monitoring: Confirmation of Train-of-four Ratio Greater than or Equal to 0.9 before Extubation
Strength	Strong
Benefit of Direction	Beneficial. Confirming a train-of-four ratio greater than or equal to 0.9 decrease the risk of residual neuromuscular blockade.
Evidence	Moderate strength of evidence. The ASA Task Force 2023 with 41 studies included in the body of evidence, European Society of Anaesthesiology and Intensive Care (ESAIC)*. RTCs comparing TOF ratios before extubation are lacking**.
Remarks	The results are consistent with less residual neuromuscular blockade when a train-of-four ratio greater than or equal to 0.9 is confirmed before extubation, but limitations in these analyses are important to note.

*The ASA Task Force 2023 [1] summary of evidence stated that patients whose train-of-four ratio was confirmed before extubation experienced less residual neuromuscular blockade compared to when the train-of-four ratio was not confirmed after neostigmine or sugammadex. The body of evidence included 41 studies (26 RTCs, 1 before–after design, 4 nonrandomized trials, 6 prospective cohort studies, 3 retrospective cohort studies, and 1 fully paired study) using quantitative monitoring and sugammadex or neostigmine and reporting residual NMB (train-of-four ratio less than 0.9) [1]. This summary of evidence coincides with those of the European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on peri-operative management of neuromuscular block [2]. **Direct evidence from randomized trials that compare confirming or not confirming train-of-four ratios before extubation are lacking.
 
When sugammadex was used and a train-of-four ratio greater than or equal to 0.9 was confirmed before extubation, the pooled incidence proportion of residual neuromuscular blockade (train-of-four ratio less than 0.9) was 0.5% (95% CI, 0.0 to 6.0%). If a train-of-four ratio greater than or equal to 0.9 was not confirmed before extubation, although quantitative monitoring was used, the incidence proportion was 2.2% (95% CI, 0.5 to 9.0%). With neostigmine, the pooled incidence proportions were 5.3% (95% CI, 2.5 to 10.7%) and 44.9% (95% CI, 29.9 to 60.8%), respectively, with and without confirmation. (https://links.lww.com/ALN/C929) displays the entirety of the results (moderate strength of evidence for train-of-four ratio greater than or equal to 0.9 confirmation before extubation) [1].
 
 Neuromuscular Monitoring: Technical Performance
 
4. We recommend using the adductor pollicis muscle for neuromuscular monitoring. (Strong, Moderate evidence)
 
5. We “recommend against” using eye muscles for neuromuscular monitoring. (Strong, Moderate evidence)
 

	Neuromuscular Monitoring: Technical Performance
Strength	Strong
Benefit of Direction	Beneficial. Complete recovery of all muscles from neuromuscular blockade (NMB) optimizes patient safety; therefore, measurements should be obtained at sites with longer times to recovery.
Evidence	Moderate strength of evidence. ASA Task Force 2023, ESAIC guideline *. Comparative, randomized and prospective observational studies**.
Remarks	Complete recovery of all muscles from neuromuscular blockade optimizes patient safety; therefore, measurements should be obtained at sites with longer times to recovery. When monitoring a muscle with relative resistance such as the eye muscles to neuromuscular blocking drugs, there is a potential for neuromuscular blocking drug overdose and for concluding that a patient is adequately antagonized when, in fact, they are not.

 
*The ASA Task Force 2023 [1] summary of evidence stated that time to reach train-of-four ratio greater than or equal to 0.9 at the adductor pollicis muscle was longer compared with eye muscles and flexor hallucis brevis. There was less residual neuromuscular blockade when patients were monitored at the adductor pollicis muscle compared to the corrugator supercilii. These recommendations are in line with those of the European Society of Anaesthesiology and Intensive Care (ESAIC) guideline [2].
 
**Comparative, randomized and prospective observational studies showed that Times to train-of-four ratio greater than or equal to 0.8, 0.9, or 1.0 were longer in patients monitored with the adductor pollicis muscles compared with the corrugator supercilii (moderate strength of evidence), orbicularis oculi (low strength of evidence), and flexor hallucis brevis muscles (very low strength of evidence) [13-16]. No difference was detected in the time to train-of-four ratio greater than or equal to 0.9 when monitoring the adductor pollicis muscle compared with the masseter (very low strength of evidence) [17].

Antagonism of Neuromuscular Blockade
 
6.  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, Moderate evidence)
 
7.  We suggest neostigmine as a reasonable alternative to sugammadex at minimal depth of neuromuscular blockade. (Conditional, Low evidence)
 

	Antagonism of Neuromuscular Blockade
Strength	Strong for sugammadex over neostigmine Conditional for neostigmine as an alternative to sugammadex at minimal depth of NMB
Benefit of Direction	Beneficial. Lower incidence of residual NMB in patients antagonized with sugammadex compared with neostigmine.
Evidence	Moderate strength of evidence for sugammadex over neostigmine. The ASA Task Force 2023, Several RCTs* Low strength of evidence for neostigmine as an alternative to sugammadex at minimal depth of NMB: Several studies and Comparative studies**.
Remarks	The FDA-approved dose recommendations for antagonizing rocuronium or vecuronium with sugammadex are 2 mg/kg for train-of-four count 2 to train-of-four ratio less than 0.9, 4 mg/kg for post-tetanic count 1 to train-of-four count 1, and 16 mg/kg immediate antagonism after administration of a single dose of rocuronium 1.2 mg/kg. A neostigmine dose of 30 µg/kg at minimal neuromuscular blockade is consistent with the FDA-approved dosage recommendations.

 
*The ASA Task Force 2023 [1] summary of evidence showed that the incidence of residual neuromuscular blockade was lower and time to recovery to Train-of-four Ratio Greater than or Equal to 0.9 was shorter with sugammadex compared to neostigmine. However, there were no differences in re-paralysis and reintubation rates. Several randomized controlled trials [18-20] reported a lower incidence of residual neuromuscular blockade in patients antagonized with sugammadex compared with neostigmine (moderate strength of evidence; https://links.lww.com/ALN/C929). Times to train-of-four ratio greater than or equal to 0.9 were shorter in patients antagonized with sugammadex compared with neostigmine from deep [21] to moderate [22,23] depths of blockade (moderate strength of evidence) and from shallow [24] (moderate strength of evidence) to minimal [21] depths of blockade (very low strength of evidence; https://links.lww.com/ALN/C929).
 
**Several studies have demonstrated that administering neostigmine at a train-of-four count of 4 is much more likely to yield a satisfactory and timely antagonism than neostigmine administered at a lower train-of-four count [25,26]. However, it is also clear from several studies that an effective antagonism is not guaranteed even when spontaneous recovery has progressed to a train-of-four count of 4 if the fourth twitch is still very weak [25]. In one study, a cohort of patients were antagonized when the train-of-four ratio was 0.4, and all patients had a timely successful antagonism as defined by a train-of-four ratio greater than or equal to 0.9 within 10 min of neostigmine administration [27]. Another study compared sugammadex with neostigmine at a train-of-four ratio of 0.5 and found that both were equally effective at this depth of blockade [28]. Additional studies have confirmed that the likelihood of an effective antagonism with neostigmine is much improved when the neuromuscular blockade is minimal (minimal block is the proposed consensus term for a quantitatively measured block with a train-of-four ratio of 0.4 to 0.9, or a qualitatively assessed block with no subjective fade to train-of-four stimulation) [28-30]. The quantitative determination of train-of-four ratio greater than or equal to 0.4 is more reliable than subjective determination of no fade with train-of-four stimulation and is associated with improved predictability of neostigmine.
 
Antagonism Strategies for Benzylisoquinolinium (Atracurium and Cisatracurium) Neuromuscular Blockade
 
8.     To avoid residual neuromuscular blockade when atracurium or cisatracurium are administered and qualitative assessment is used, we suggest antagonism with neostigmine at minimal neuromuscular blockade depth. In the absence of quantitative monitoring, at least 10 min should elapse from antagonism to extubation. When quantitative monitoring is utilized, extubation can be done as soon as a train-of-four ratio greater than or equal to 0.9 is confirmed before extubation. (Conditional, Very low evidence)
 

	Antagonism strategies for benzylisoquinolinium (atracurium and cisatracurium) neuromuscular blockade
Strength	Conditional
Benefit of Direction	Beneficial. Safe full antagonism strategies for benzylisoquinolinium (atracurium and cisatracurium) NMB
Evidence	Very low strength of evidence: The ASA Task Force 2023, Six studies*.
Remarks	Benzylisoquinolinium neuromuscular blocking drugs (cisatracurium and atracurium) can be antagonized only with an acetylcholinesterase inhibitor such as neostigmine—sugammadex is ineffective.

 
*The ASA Task Force 2023 [1] summary of evidence showed that times to train-of-four ratio greater than or equal to 0.9 after neostigmine administration ranged from 1 to 143 min reported in six studies [31, 25, 27, 32-34] (https://links.lww.com/ALN/C929; very low strength of evidence). Time to train-of-four ratio greater than or equal to 0.9 for neostigmine antagonism of cisatracurium and atracurium showed a mean, min (SD) time of 10.3 (1.3) min [32] and wide range for Median, min (Range) from 4 (3-6) [27] to 16.5 (6.5-143.3) [25]
 
Benzylisoquinolinium NMB drugs (cisatracurium and atracurium) can be antagonized only with an acetylcholinesterase inhibitor such as neostigmine—sugammadex is ineffective. However, neostigmine can be accompanied by a longer time to recovery than may be recognized. Assuming that (i) neostigmine is given once a muscle relaxant is no longer required for surgery, (ii) there is some spontaneous recovery from neuromuscular blockade, and (iii) emergence from anesthesia is expected in approximately 10 min, antagonism success depends primarily on the depth of block at the time of administration. Full antagonism within 10 min is most likely when neostigmine is given with four twitches and no visible or tactile fade. Success is unlikely when given with fewer than four twitches. Under these circumstances limited evidence is consistent with a median time to antagonism less than 10 min, but with a wide range in time to recovery from a train-of-four ratio of less than 0.4 to a train-of-four count 2 to 3 blockade [25, 27, 31-34]. Therefore, verifying adequate recovery necessitates measuring train-of-four ratio with a quantitative monitor.