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# Guidelines on muscle relaxants and reversal in anaesthesia

Benoît Plaud, Christophe Baillard, Jean Louis Bourgain, Gaëlle Bouroche, Laetitia Desplanque, Jean Michel Devys, Dominique Fletcher, Thomas Fuchs-Buder, Gilles Lebuffe, Claude Meistelman, et al.

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## To cite this version:

Benoît Plaud, Christophe Baillard, Jean Louis Bourgain, Gaëlle Bouroche, Laetitia Desplanque, et al. Guidelines on muscle relaxants and reversal in anaesthesia. Anaesthesia Critical Care & Pain Medicine, 2020, 39 (1), pp.125-142. 10.1016/j.accpm.2020.01.005. hal-03227897

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# Guidelines

## Guidelines on muscle relaxants and reversal in anaesthesia☆,☆☆

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Benoît Plaud<sup>a,*,1</sup>, Christophe Baillard<sup>b,1</sup>, Jean-Louis Bourgain<sup>c</sup>, Gaëlle Bouroche<sup>d</sup>, Laetitia Desplanque<sup>e</sup>, Jean-Michel Devys<sup>f</sup>, Dominique Fletcher<sup>g,2</sup>, Thomas Fuchs-Buder<sup>h</sup>, Gilles Lebuffe<sup>i</sup>, Claude Meistelman<sup>h</sup>, Cyrus Motamed<sup>c</sup>, Julien Raft<sup>j</sup>, Frédérique Servin<sup>e</sup>, Didier Sirieix<sup>k</sup>, Karem Slim<sup>l</sup>, Lionel Velly<sup>m,2</sup>, Franck Verdonk<sup>n</sup>, Bertrand Debaene<sup>o,1</sup>

## ARTICLE INFO

Article history:

Available online 8 January 2020

Keywords:

Muscle relaxants

Reversal

Neuromuscular

Monitoring

Update of expert guidelines

## ABSTRACT

**Objectives:** To provide an update to the 1999 French guidelines on "Muscle relaxants and reversal in anaesthesia", a consensus committee of sixteen experts was convened. A formal policy of declaration and monitoring of conflicts of interest (COI) was developed at the outset of the process and enforced throughout. The entire guidelines process was conducted independently of any industrial funding (i.e. pharmaceutical, medical devices). The authors were required to follow the rules of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE®) system to assess the quality of the evidence on which the recommendations were based. The potential drawbacks of making strong recommendations based on low-quality evidence were stressed. Few of the recommendations remained ungraded.

**Methods:** The panel focused on eight questions: (1) In the absence of difficult mask ventilation criteria, is it necessary to check the possibility of ventilation via a facemask before muscle relaxant injection? Is it necessary to use muscle relaxants to facilitate facemask ventilation? (2) Is the use of muscle relaxants necessary to facilitate tracheal intubation? (3) Is the use of muscle relaxants necessary to facilitate the insertion of a supraglottic device and management of related complications? (4) Is it necessary to monitor neuromuscular blockade for airway management? (5) Is the use of muscle relaxants necessary to facilitate interventional procedures, and if so, which procedures? (6) Is intraoperative monitoring of neuromuscular blockade necessary? (7) What are the strategies for preventing and treating residual neuromuscular blockade? (8) What are the indications and precautions for use of both muscle relaxants and reversal agents in special populations (e.g. electroconvulsive

<footnote><sup>a</sup>Université de Paris, Assistance publique-Hôpitaux de Paris, service d'anesthésie et de réanimation, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France</footnote>

<footnote><sup>b</sup>Université de Paris, Assistance publique-Hôpitaux de Paris, service d'anesthésie et de réanimation, hôpital Cochin-Port Royal, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France</footnote>

<footnote><sup>c</sup>Institut Gustave-Roussy, service d'anesthésie, 114, rue Édouard-Vaillant, 94800 Villejuif, France</footnote>

<footnote><sup>d</sup>Centre Léon-Bérard, service d'anesthésie, 28, promenade Léa-et-Napoléon-Bullukian, 69008 Lyon, France</footnote>

<footnote><sup>e</sup>Assistance publique-Hôpitaux de Paris, service d'anesthésie et de réanimation, hôpital Bichat-Claude-Bernard, 46, rue Henri-Huchard, 75877 Paris cedex, France</footnote>

<footnote><sup>f</sup>Fondation optalmologique Adolphe-de-Rothschild, service d'anesthésie et de réanimation, 29, rue Manin, 75019 Paris, France</footnote>

<footnote><sup>g</sup>Université de Versailles-Saint-Quentin-en-Yvelines, Assistance publique-Hôpitaux de Paris, hôpital Ambroise-Paré, service d'anesthésie, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France</footnote>

<footnote><sup>h</sup>Université de Lorraine, CHU de Brabois, service d'anesthésie et de réanimation, rue du Morvan, 54511 Vandœuvre-lès-Nancy, France</footnote>

<footnote><sup>i</sup>Université de Lille, hôpital Huriez, service d'anesthésie et de réanimation, rue Michel-Polonovski, 59037 Lille, France</footnote>

<footnote><sup>j</sup>Institut de cancérologie de Lorraine, service d'anesthésie, 6, avenue de Bourgogne, 54519 Vandœuvre-lès-Nancy, France</footnote>

<footnote><sup>k</sup>Groupe polyclinique Marzet-Navarre, service d'anesthésie, 40, boulevard d'Alsace-Lorraine, 64000 Pau, France</footnote>

<footnote><sup>l</sup>Université d'Auvergne, service de chirurgie digestive et hépatobiliaire, hôpital d'Estaie, 1, rue Lucie-Aubrac, 63100 Clermont-Ferrand, France</footnote>

<footnote><sup>m</sup>Université Aix-Marseille, hôpital de la Timone adultes, service d'anesthésie et de réanimation, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France</footnote>

<footnote><sup>n</sup>Sorbonne université, hôpital Saint-Antoine, 84, rue du Faubourg-Saint-Antoine, 75012 Paris, France</footnote>

<footnote><sup>o</sup>Université de Poitiers, service d'anesthésie et de réanimation, CHU de Poitiers, BP 577, 86021 Poitiers cedex, France</footnote>

<footnote>* Updated guidelines from the French Society of Anaesthesia & Intensive Care Medicine (Société française d'anesthésie et de réanimation - SFAR).</footnote>

<footnote>** Text approved by the SFAR's board of directors (21/06/2018) and presented at the SFAR's annual meeting (29/09/2018).</footnote>

<footnote>* Corresponding author.
E-mail address: benoit.plaud@aphp.fr (B. Plaud).</footnote>

<footnote n="1">¹ SFAR expert coordinators.</footnote>

<footnote n="2">² Organisers.</footnote>
therapy, obese patients, children, neuromuscular diseases, renal/hepatic failure, elderly patients)? All questions were formulated using the Population, Intervention, Comparison and Outcome (PICO) model for clinical questions and evidence profiles were generated. The results of the literature analysis and the recommendations were then assessed using the GRADE® system.

*Results:* The summaries prepared by the SFAR Guideline panel resulted in thirty-one recommendations on muscle relaxants and reversal agents in anaesthesia. Of these recommendations, eleven have a high level of evidence (GRADE 1±) while twenty have a low level of evidence (GRADE 2±). No recommendations could be provided using the GRADE® system for five of the questions, and for two of these questions expert opinions were given. After two rounds of discussion and an amendment, a strong agreement was reached for all the recommendations.

*Conclusion:* Substantial agreement exists among experts regarding many strong recommendations for the improvement of practice concerning the use of muscle relaxants and reversal agents during anaesthesia. In particular, the French Society of Anaesthesia and Intensive Care (SFAR) recommends the use of a device to monitor neuromuscular blockade throughout anaesthesia.

© 2020 The Authors. Published by Elsevier Masson SAS on behalf of Société française d'anesthésie et de réanimation (Sfar). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## SFAR organisers and expert coordinators

Christophe Baillard, Bertrand Debaene, Benoît Plaud

## Organising committee

Dominique Fletcher, Lionel Velly

## SFAR experts group

Christophe Baillard, Jean-Louis Bourgain, Gaëlle Bouroche, Bertrand Debaene, Jean-Michel Devys, Thomas Fuchs-Buder, Gilles Lebuffe, Claude Meistelman, Cyrus Motamed, Benoît Plaud, Julien Raft, Frédérique Servin, Didier Sirieix, Karem Slim

## Reading group

**SFAR Guidelines committee:** Julien Amour, Alice Blet, Gérald Chanques, Vincent Compère, Philippe Cuvillon, Fabien Espitalier, Marc Garnier, Etienne Gayat, Hervé Quintard, Bertrand Rozec, Lionel Velly, Emmanuel Weiss

**SFAR board of directors:** Xavier Capdevila, Hervé Bouaziz, Laurent Delaunay, Pierre Albaladejo, Jean-Michel Constantin, Marie-Laure Cittanova-Pansard, Marc Léone, Bassam Al Nasser, Valérie Billard, Francis Bonnet, Julien Cabaton, Marie-Paule Chariot, Isabelle Constant, Alain Delbos, Claude Ecoffey, Jean-Pierre Estèbe, Marc Gentili, Olivier Langeron, Pierre Lanot, Luc Mercadal, Karine Nouette-Gaulain, Jean-Christian Sleth, Eric Viel, Paul Zetlaoui

# 1. Introduction

The consensus conference (CC) on "indications for muscle relaxant use in anaesthesia" was conducted in 1999 and its findings were published in 2000 [1]. It specified the conditions of use of muscle relaxants for endotracheal intubation and surgical intervention, as well as their side effects and the safety rules during perioperative use of muscle relaxants and reversal agents. The target populations were adults and children. Muscle relaxant use was also discussed at other CCs and expert conferences (ECs), including those on airway control: "Airway management during adult anaesthesia, other than for difficult intubation" [2], "Difficult intubation" [3], "Pre-hospital sedation and analgesia" [4], and "Sedation and analgesia in resuscitation" [5].

These reference documents argued in favour of the positive effects of muscle relaxant use on intubation conditions for both health care providers and patients, particularly in adults.

Several new elements have emerged since this initial CC on the "indications for muscle relaxant use in anaesthesia" [1], such as:

* the possibility of administering a non-depolarising muscle relaxant, both with and without prior verification of the ability to provide effective ventilation via a mask;

* the positive effects of muscle relaxant use on intubation conditions for both health care providers and patients, including in paediatrics and electroconvulsive therapy;

* the development of alternatives to intubation such as supra-glottic devices to achieve airway control;

* the rise of laparoscopic surgery, with and without robotic assistance;

* regularly updated epidemiological data concerning allergic risk associated with muscle relaxants, which were reviewed in the formalised expert recommendations on "Reducing the risk of anaphylaxis during anaesthesia" [6];

* recent data on precautions for use of suxamethonium that led to a modification of the Summary of Product Characteristics (SPC) by the Agence nationale de sécurité du médicament et des produits de santé (ANSM) [7];

* market withdrawal of certain muscle relaxant compounds (pancuronium, vecuronium) and the availability of cisatracurium;

* epidemiological assessment of morbidity-mortality related to non-compliant practices in rapid-sequence induction (anaesthesia, emergency and pre-hospital settings);

* the positive impact of neuromuscular monitoring on management of neuromuscular blockade, poor performance of clinical reversal tests for the detection of residual neuromuscular blockade;

* regular international updating of data on the frequency of residual neuromuscular blockade, with and without pharmacological reversal, and consequences of the latter being associated with excess risk of severe morbidity immediately following anaesthesia;

* the development of new methods for objective neuromuscular blockade monitoring for routine clinical use;

* review of the effects of neostigmine, especially in terms of timing and required spontaneous recovery, time-to-peak effect;

* the possibility of dose reduction in certain cases and initial data on the use of sugammadex, a selective reversal agent for steroidal muscle relaxants.
Regarding the risk-benefit ratio relative to the use of muscle relaxants, the experts remind us that, for more than thirty years now, all studies investigating intraoperative allergic accidents in France have been pointing in the same direction. Muscle relaxants have been involved in over half of these accidents [8,9]. Among these muscle relaxants, rocuronium and suxamethonium have been more frequently incriminated than others. In the study by Mertes et al. [10], for 373 cases of documented allergy to muscle relaxants, rocuronium was involved in 16 cases and suxamethonium in 226 cases. Taking market share into consideration, rocuronium was responsible for 4.6% of accidents involving allergy to muscle relaxants, whilst representing only 1.1% of the market share. Suxamethonium, with a market share of 12.2%, was responsible for 60.6% of accidents involving allergy to muscle relaxants. By comparison, atracurium has a market share of 45.2% and is responsible for 19.6% of accidents involving allergy to muscle relaxants. Also considering market share, the frequency of rocuronium anaphylaxis was estimated at 8.0/100,000 administrations, vs. 2.8/100,000 for vecuronium and 4.0/100,000 for atracurium. The incidence for suxamethonium could not be determined [11,12]. More recently, the frequency of anaphylaxis due to atracurium has been estimated at 1/22,451 administrations vs. 1/2080 for suxamethonium and 1/2499 for rocuronium [13]. French pharmacovigilance centres (unpublished data transcribed with the permission of the ANSM) have confirmed these data. Out of 1624 cases analysed, only those with positive tryptase and skin tests were selected, i.e. 680 cases. Suxamethonium had a notification rate of 7.05/100,000 administrations vs. 4.15/100,000 for rocuronium. Other muscle relaxants had notification rates of 0.17/100,000 to 0.36/100,000. Two distinct groups were confirmed: suxamethonium and rocuronium, which had higher notification rates, and other muscle relaxants, which had lower notification rates.

## 2. Methods

### Literature search and selection criteria

The literature search focused on publications referenced in Medline® and the Cochrane database® with no time limits. The selection focused on controlled trials, meta-analyses, systematic reviews and cohort studies. A specific analysis of the paediatric literature was carried out.

### Population and comparisons

The populations under study included adults, children and special populations such as obese patients, patients with renal/hepatic dysfunction, and patients with neuromuscular diseases. These different situations are analysed separately.

### The GRADE® system

Each question was formulated using the Patients, Intervention, Comparison and Outcome (PICO) model. The method used to develop the recommendations is the Grading of Recommendations, Assessment, Development and Evaluation (GRADE®) system. After a quantitative analysis of the literature, this method allows separate determination of the quality of the evidence, i.e. an estimation of the confidence that may be had in analysing the effects of the quantitative intervention, as well as a recommendation level. Quality of evidence was divided into four categories:

* high: future research will most likely not change confidence in the estimated effect;

* moderate: future research is likely to change confidence in the estimated effect and might alter the estimated effect itself;

* low: future research will most likely have an impact on confidence in the estimated effect and will probably alter the estimate of the effect itself;

* very low: the estimated effect is very uncertain.

A quality-of-evidence analysis was conducted for each study and an overall level of evidence was defined for a given question and criterion. The final formulation of the recommendations will always be binary, i.e. either positive or negative and either strong or weak:

* strong recommendation: we recommend/do not recommend (GRADE 1+ or 1-);

* weak recommendation: we suggest/do not suggest (GRADE 2+ or 2-).

The strength of a recommendation is influenced by key factors and validated through voting by the experts using the Delphi method and GRADE® grids:

* estimate of the effect;

* overall level of evidence: the higher the level, the stronger the recommendation;

* the balance between desirable and adverse effects: the more favourable the balance, the higher the recommendation. The narrower the gradient, the more likely a weak recommendation is warranted;

* values and preferences: in the event of uncertainties or great variability, the recommendation will most likely be weak. These values and preferences must be obtained directly from the people involved (patient, doctor, decision-maker);

* costs: the higher the costs or the use of resources, the weaker the recommendation;

* to develop a recommendation, at least 50% of participants must have one opinion and less than 20% the opposite opinion;

* to develop a strong recommendation, at least 70% of participants must agree (grade between 7 and 10).

In some cases, it was impossible to propose a recommendation.

If the experts did not have enough data from the literature to allow them making a recommendation, an expert opinion was then proposed and, if at least 70% of the experts agreed with the proposal, it was approved.

The summaries prepared by the experts and application of the GRADE® system resulted in thirty-one recommendations being made. Among the formalised recommendations, eleven have a high level of evidence (GRADE 1±) and twenty have a low level of evidence (GRADE 2±). For five recommendations, the GRADE® method could not be applied, and expert advice was provided for two of them. After two rounds of scoring and an amendment, strong agreement was reached for all the recommendations.

These French Expert Recommendations (FERs) supersede the previous recommendations from the French Society of Anaesthesia & Intensive Care Medicine (SFAR) and have the same scope. The SFAR encourages all anaesthetists to comply with these FERs to ensure the quality of patient care. However, in applying these recommendations, individual practitioners must exercise their own judgment, based on their personal expertise and the specific features of their institution, when determining the intervention method best suited to the actual condition of their patients.

The questions tackled in these Guidelines updates are as follows:

* in the absence of difficult mask ventilation criteria is it necessary to check the possibility of ventilation via a facemask before muscle relaxant injection? Is it necessary to use muscle relaxants to facilitate facemask ventilation?

* is the use of muscle relaxants necessary to facilitate tracheal intubation?
* is the use of muscle relaxants necessary to facilitate the insertion of a supraglottic device and management of related complications?

* is it necessary to monitor neuromuscular blockade for airway management?

* is the use of muscle relaxants necessary to facilitate interventional procedures, and if so, which procedures?

* is intraoperative monitoring of neuromuscular blockade necessary?

* what are the strategies for preventing and treating residual neuromuscular blockade?

* what are the indications and precautions for use of both muscle relaxants and reversal agents in special populations?

**Question 1: In the absence of difficult mask ventilation criteria is it necessary to check the possibility of ventilation via a facemask before muscle relaxant injection? Is it necessary to use muscle relaxants to facilitate facemask ventilation?**

PICO. P = "adult patients receiving muscle relaxants for surgery involving tracheal intubation", I = "muscle relaxants (muscle relaxant type: suxamethonium, atracurium, vecuronium and rocuronium)", C = "no muscle relaxants", O = "measurement of respiratory mechanical parameters (VT, insufflation pressure)". For the question "Is it necessary to use muscle relaxants to facilitate face mask ventilation?", O = "quality scale for face mask ventilation."

**R1.1** – It is probably not recommended to verify the possibility of mask ventilation before administering a muscle relaxant.
(GRADE 2–) STRONG AGREEMENT

**R1.2** – It is probably recommended to administer a muscle relaxant to facilitate facemask ventilation.
(GRADE 2+) STRONG AGREEMENT

Rationale

Safety is provided by the use of oxygenation methods immediately available prior to the onset of desaturation (SpO₂ < 95%). Regardless of the induction protocol, with or without a muscle relaxant, the safety margin between apnoea duration and O₂ reserves is small. This situation is all the more common with a high body mass index and high O₂ consumption. Testing mask ventilation quality before injecting a muscle relaxant increases the duration of induction by adding the time it takes for the muscle relaxant to work to that of the other anaesthetic agents.

Testing the quality of mask ventilation before administering a muscle relaxant may be proposed bearing in mind that:

* injecting a muscle relaxant may lengthen the duration of apnoea and induce desaturation due to the inability to ventilate with the mask;

* it must be possible to wake up the patient at any time if the situation so warrants.

The need to wake up a patient due to the inability to intubate is extremely rare and poorly documented: there have been only two cases out of 100 difficult intubations among 11,257 intubations [14] and nine cases among 698 patients with both difficult intubation and mask ventilation [15]. Rapid recovery of spontaneous ventilation after induction does not prevent the occurrence of oxygen desaturation [16], which justifies maintaining a high O₂ reserve at all times.

Neuromuscular blockade does not necessarily increase apnoea duration and risk of desaturation. Following administration of thiopental and suxamethonium in healthy volunteers, four out of twelve subjects showed a decrease in oxygen saturation to below 80% before recovery of neuromuscular blockade. Among twenty-four healthy volunteers, injection of propofol 2.0 mg/kg and remifentanil 1.5 or 2.0 µg/kg resulted in profound desaturation in five subjects (four in the 2.0 µg/kg group and one in the 1.5 µg/kg group) [17]. Increasing the dose of remifentanil from 1.0 to 2.0 µg/kg increased apnoea time substantially (270 s to 487 s) while around 10% of patients had intubation conditions deemed unacceptable [18]. Using remifentanil at a dose of 4 µg/kg provides intubation conditions comparable to those observed after suxamethonium at the expense of blood pressure lowering, and an increase in duration of apnoea (12.8 min vs. 6.0 min) [19]. All publications report the use of propofol at doses between 2.0 and 2.5 mg/kg. The return to consciousness judged on the response to simple orders and the bi-spectral index (BIS) is 529 s (standard deviation 176 s) after injecting 2 mg/kg of propofol [20]. Nevertheless, awakening does not imply disappearance of the effects of propofol on the laryngeal muscles; the latter remain measurable for concentrations of as low as 0.7 µg/mL [21]. The effect of suxamethonium has been evaluated as lasting seven to eight minutes long using laryngeal and diaphragmatic electromyography [22] and about twelve minutes using accelerometry [23], with significant variability in both cases.

Reducing the dose of suxamethonium does not significantly shorten this apnoea time [24]. Use of sugammadex after rocuronium results in a faster and more reliable recovery time than use of suxamethonium [23], if the right number of vials of sugammadex is immediately available [25]. Injecting sugammadex after rocuronium gives better results than suxamethonium in terms of mean value (4.7 min) and individual variability [23]. Neuromuscular blockade reversal using sugammadex may be ineffective and lead to a situation requiring emergency tracheal access [26].

Does a muscle relaxant impair mask ventilation in patients without difficult mask ventilation criteria and/or difficult intubation? Muscle relaxant administration improves muscle relaxation especially when using high doses of sufentanil [27] or remifentanil [28] or low doses of a hypnotic [29]. Five studies investigated the effect of muscle relaxant injection on respiratory mechanics, and all used different criteria. Two of these included a small number of patients (30 and 32, respectively) and reported non-significant [30] or slightly significant results in favour of suxamethonium [31]. Interindividual variability in muscle relaxant response is important, suggesting that some patients are already fully relaxed before paralysis. In two studies (125 patients, some of whom were obese [32], and 210 patients [33]), the improvement in ventilation after neuromuscular blockade was significant, although impairment was seen in 19% of them [33]. Improved mask ventilation was also brought to light on objective criteria after injecting rocuronium [34].

Based on a database of four hospitals including 492,239 general anaesthesias, the combination of mask ventilation difficulty and intubation difficulty was reported in 698 patients (0.4%) [15]. Improved mask ventilation after neuromuscular blockade was observed for 19 patients, with no worsening. In a prospective series of 12,225 patients with difficult intubation criteria, improved ventilation after muscle relaxant injection was noticed in 56 out of 90 patients presenting difficult mask ventilation (with no impairment for the others) [35].

**Question 2: Is the use of muscle relaxants necessary to facilitate tracheal intubation?**

PICO. P = "adult patients receiving muscle relaxants for a scheduled procedure with tracheal intubation", I = "muscle
relaxants (muscle relaxant type: suxamethonium, atracurium, cisatracurium, mivacurium, pancuronium, rapacuronium, vecuronium and rocuronium)”, C = “no muscle relaxants”, O = either positive, for “assessment of intubation conditions, either by the criteria of Cormack and Lehane” [36,37] or those of the “Good Clinical Research Practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents” [38], or negative, for “upper respiratory discomfort: sore throat, hoarseness, vocal cord injury, pharyngeal injury, dental injury, severe complications: tracheal perforation, oesophageal intubation, inhalation lung disease, allergic reaction.”

**R2.1** – The use of a muscle relaxant is recommended to facilitate tracheal intubation.

(GRADE 1+) STRONG AGREEMENT

Rationale

Since the 1999 consensus conference, several studies have examined the issue of whether muscle relaxants facilitate tracheal intubation. To this end, thirty-two randomised and controlled studies, a cohort study and a systematic review were analysed [19,39–70]. The muscle relaxants currently available in France (from the oldest to the most recent) are suxamethonium, atracurium, rocuronium, mivacurium and cisatracurium. Studies involving doses of muscle relaxant below the 95% effective dose (ED<sub>95</sub>) at the adductor pollicis were not considered. If several doses of the same muscle relaxant were used per study, the dose closest to twice the ED<sub>95</sub> was retained. For those studies comprising several protocols without a muscle relaxant, a second analysis was conducted considering only the best protocol. This is how data from 1247 patients who had received a muscle relaxant and 1422 who had not received a muscle relaxant (best protocol analysis: 1092 patients) were analysed for a total of 2669 patients (best protocol analysis: 2339 patients). Without a muscle relaxant, 350 patients (best protocol analysis: 283 patients) presented poor intubating conditions. This corresponds to a rate of 24.6% (best protocol analysis: 25.9%). With a muscle relaxant, 51 patients (4.1%) had poor intubating conditions. The cohort involved 103,784 patients, of whom 28,201 were intubated without and 75,583 with a muscle relaxant. Without a muscle relaxant, the rate of poor intubating conditions was 6.7% vs. 4.5% using a muscle relaxant. This study identified muscle relaxant-free intubation as an independent risk factor for difficult intubation. As a result, these data support the concept that, compared with a muscle relaxant-free protocol, the use of a muscle relaxant facilitates tracheal intubation.

**R2.2** – The use of a muscle relaxant is recommended to reduce pharyngeal and/or laryngeal injury.

(GRADE 1+) STRONG AGREEMENT

Rationale

The quality of intubation can have clinical consequences for the patient. Mencke et al. [56] established a link between intubation quality and postoperative complications such as vocal cord damage and hoarseness. Six randomised controlled studies in 746 patients (best protocol analysis: 694 patients) were analysed [42,43,45,56,57,66]. According to these studies, 90 patients (best protocol analysis: 65 patients) sustained pharyngeal and/or laryngeal injuries. This corresponds to a rate of 22.6% (best protocol analysis: 18.7%). By using a protocol with a muscle relaxant, this incidence could be reduced to 9.7%. This reduction in pharyngeal and/or laryngeal lesions was seen in all six studies

analysed. The absence of a muscle relaxant to facilitate intubation increases the risk of upper respiratory injury or discomfort. While a pharyngeal and/or laryngeal injury rate of nearly 10% despite good intubating conditions may be surprising, these complications may be caused by several factors other than intubating conditions. The most important are certainly the tracheal tube size and extubation conditions.

**R2.3** – Administration of a short-acting muscle relaxant for rapid-sequence induction is probably recommended.

(GRADE 2+) STRONG AGREEMENT

Rationale

Rapid-sequence induction, whatever the indication, consists of minimising the time between loss of consciousness and correct insertion of the tracheal tube in order to avoid positive pressure ventilation via the face mask and prevent the risk of inhaling gastric content. To achieve this goal, the fastest acting anaesthetic drugs are preferred. When a neuromuscular blocking drug is associated to facilitate tracheal intubation, it must meet the same requirement, i.e. generate paralysis within the shortest possible onset time. Suxamethonium is traditionally used in this indication because it has the shortest onset time and the shortest duration of action of all available muscle relaxants. It has numerous side effects, some of which are serious. Rocuronium is the non-depolarising muscle relaxant with the shortest onset time and has been proposed as an alternative to suxamethonium. A meta-analysis of the Cochrane Library analysed and compared the intubating conditions arising after administration of suxamethonium and rocuronium [8]. Fifty publications (controlled and randomised trials or controlled clinical trials) involving 4151 patients were analysed. Suxamethonium provides excellent intubation conditions more frequently than rocuronium (RR = 0.86; 95% confidence interval: 0.81–0.92; I² = 72%). In a subgroup analysis comparing suxamethonium 1.0 mg/kg with rocuronium at a dose greater than 0.9 mg/kg, no superiority of suxamethonium was found. However, the heterogeneity noted between the different studies warrants a GRADE 2 level for the recommendation.

**Question 3: Is the use of muscle relaxants necessary to facilitate the insertion of a supraglottic device and management of related complications?**

PICO. P = “adult patients receiving muscle relaxants for a scheduled procedure involving a supraglottic device”, I = “muscle relaxants (muscle relaxant type: suxamethonium, atracurium, vecuronium and rocuronium)”, C = “no muscle relaxants or before – after”, O = “measurement of respiratory mechanical parameters (VT, insufflation pressure) and success rate of laryngeal mask positioning or recovery of airway patency”.

**R3.1** – Routine use of a muscle relaxant to facilitate insertion of a supraglottic device is probably not recommended.

(GRADE 2–) STRONG AGREEMENT

Rationale

Without muscle relaxant, the success rate of laryngeal mask insertion is commonly high and ventilation conditions are often satisfactory [71,72]. Neuromuscular blockade is probably useful when inserting a supraglottic device when the doses of hypnotic and opioid agents used for induction are low [73,74]. Anaesthesia protocols that exclude propofol as an induction agent have a high
rate of adverse insertion events whose incidence decreases with neuromuscular blockade [75,76]. No publications have reported any adverse effects of neuromuscular blockade on the quality of ventilation. The overall level of evidence in the literature remains low due to the heterogeneity of the anaesthesia protocols used and their outcomes.

**R3.2** – Administration of a muscle relaxant in case of airway obstruction related to a supraglottic device is probably recommended.

(GRADE 2+) STRONG AGREEMENT

## Rationale

In the event of upper airway obstruction, administering a muscle relaxant is proposed in the same way as a change in supraglottic device size or adjustment of position [77]. Two clinical entities must be distinguished: glottic closure resulting in incomplete or easily reversible obstruction, and laryngospasm involving complete glottic closure which is irreducible using the standard methods of ventilation [78]. Muscle relaxation is highly recommended during laryngospasm even if injection of propofol (0.25 to 0.8 mg/kg) is effective in the majority of cases (77%) [79]. In the absence of a muscle relaxant, muscle relaxation under general anaesthesia is not always complete. Moreover, opioids tend to increase muscle tone [28]. In the event of glottic closure not related to laryngospasm, the administration of a muscle relaxant is useful after providing sufficiently deep anaesthesia. The best agent is suxamethonium, which is effective in all cases [80]. In addition, it is fast-acting, and the laryngeal muscles are particularly sensitive to it [81]. It is most often given intravenously (1.0 mg/kg) but intramuscular and even sublingual administrations have been proposed (4.0 mg/kg) [82,83]. In children under three years of age, atropine (0.02 mg/kg) is usually associated to avoid bradycardia or even cardiac arrest [80]. It is essential to be aware of the adverse effects of suxamethonium and to comply with the contraindications of the drug [82,84]. Comparable efficacy may possibly be achieved with a non-depolarising muscle relaxant because low concentrations of muscle relaxant are required to relax the laryngeal muscles [84]. A low dose is sufficient to achieve glottic opening if the depth of anaesthesia is adequate (rocuronium or atracurium 0.1 to 0.2 mg/kg) [28,85]. In all cases, reduction of complications associated with upper airway obstruction is optimised when it is integrated within a quality approach. The immediate availability of suxamethonium and atropine, especially in paediatric operating theatres, is crucial as when combined with neuromuscular blockade for intubation, it reduces the incidence of cardiac arrest and severe airway obstruction accidents nearly by half [86].

## Question 4: Is it necessary to monitor neuromuscular blockade for airway management?

PICO. P = "adult patients receiving non-depolarising muscle relaxants for a scheduled procedure with tracheal intubation", I = "muscle relaxants (muscle relaxant type: atracurium and rocuronium)", C = "no monitoring", O = "assessment of intubation conditions, using either the Cormack & Lehane criteria [36,37] or those of Good Clinical Research Practice (GCRP) in Pharmacodynamic Studies of Neuromuscular Blocking Agents" [38].

**No recommendation** - Data in the literature are insufficient to establish any recommendations on the use of instrumental monitoring of neuromuscular blockade during tracheal intubation.

## Rationale

There are no studies supporting a recommendation concerning the relevance of neuromuscular monitoring for intubation compared to a fixed time following injection of rocuronium or atracurium.

**R4.1** – The experts suggest that if instrumental neuromuscular blockade monitoring is used, the selected site should be the corrugator supercilii muscle because of its sensitivity to muscle relaxants and its kinetics of neuromuscular blockade, which are comparable to those of laryngeal muscle.

**EXPERT OPINION**

## Rationale

Intubating conditions are worse when the orbicularis oculi is used to decide when to perform tracheal intubation compared to when the corrugator supercilii or the adductor pollicis are used [87,88]. Poor intubating conditions are only found in the group of patients with orbicularis oculi monitoring. The onset time of maximum neuromuscular blockade at the corrugator supercilii is comparable to that of the laryngeal adductor muscles, whereas that of the orbicularis oculi corresponds much more closely to those of muscles which are more sensitive to muscle relaxants (e.g. adductor pollicis) [89]. Under the same intubating conditions, corrugator supercilii monitoring reduces the time taken to achieve tracheal intubation compared to adductor pollicis monitoring [90,91]. These latter two studies indicate the use of the orbicularis oculi instead of the corrugator supercilii. In fact, it was the corrugator supercilii that was assessed. With atracurium or rocuronium administered at a suitable dose for tracheal intubation, the fact of systematically waiting for the mean onset time to elapse before starting laryngoscopy ensures the best conditions for intubation.

## Question 5: Is the use of muscle relaxants necessary to facilitate interventional procedures and, if so, which ones?

PICO. P = "adult patients receiving muscle relaxants to allow scheduled surgical procedure", I = "muscle relaxants", C = "no muscle relaxants or moderate neuromuscular blockade", O = "surgical field quality score, laparoscopic insufflation pressure".

**R5.1** – The use of muscle relaxants is recommended to facilitate interventional procedures in abdominal laparotomy or laparoscopy surgery.

(GRADE 1+) STRONG AGREEMENT

**R5.2** – The use of muscle relaxants is probably recommended to facilitate interventional procedures in ENT laser surgery.

(GRADE 2+) STRONG AGREEMENT

## Rationale

Most articles published on this topic are to do with abdominal surgery. Three studies involving, respectively, laparotomy prostate surgery [92] laparoscopic cholecystectomies and hysterectomies with a control group receiving placebo or a low dose of muscle relaxant, highlighted an improvement in surgical conditions with intraoperative neuromuscular blockade [93,94]. In laparoscopic surgery, neuromuscular blockade may be useful at the time of pneumoperitoneum establishment to help prevent iatrogenic accidents related to trocar insertion, increase the working space and during aponeurotic closure of trocar incisions. In abdominal
surgery, a deep neuromuscular blockade may improve operating conditions by allowing adequate exposure during laparotomy and, to an even greater extent, during laparoscopy [95-97]. Regarding laryngeal surgery, the results are in favour of a deep neuromuscular blockade with a statistically significant difference regarding exposure of the surgical field (as assessed by the surgeon), intraoperative vocal cord movements and postoperative oral dryness, but with no difference regarding postoperative adverse events [98,99].

**No recommendation** - Data in the literature are insufficient to be able to establish a recommendation on the required intensity of neuromuscular blockade (moderate vs. deep) in abdominal laparotomy or laparoscopy surgery.

## Rationale

A few studies have shown the beneficial effect of a deep neuromuscular blockade on surgical conditions from a surgical standpoint. The absolute difference between a deep and a moderate blockade for obtaining good or excellent operating conditions is 25%, i.e. in these studies, one in four patients would have benefited from a deep blockade in terms of operating conditions [100-102]. The question raised by this difference is: which patients should benefit from the deep neuromuscular blockade? So far, the literature has provided no answers to this question. Studies in non-abdominal surgery have concerned spinal surgery but shown no benefits for the deep neuromuscular blockade compared to the moderate blockade [103,104]. However, no trials have shown any difference between the deep blockade and the moderate blockade in terms of intraoperative adverse surgical events or specific morbidity associated with poor exposure. Nevertheless, this lack of difference should be interpreted with caution as the trials all had small sample sizes (n = 24 to 102), which were insufficient to reveal any significant difference. It is therefore impossible to make a recommendation on the depth of neuromuscular blockade required to achieve a reduction in intraoperative and postoperative surgical morbidity. The experts only found a few studies focusing on the reduction of pneumoperitoneum pressure according to the depth of neuromuscular blockade: moderate (1 to 2 TOF responses at the adductor pollicis) or deep [1-2 post-tetanic count (PTC) responses at the adductor pollicis]. The randomised study by Madsen et al. (n = 14) showed that a deep blockade increased the distance between the umbilical trocar and the promontory by 0.3 cm. This difference is not clinically significant, and the study did not evaluate the risk associated with inserting the first trocar [97]. Three randomised prospective studies were retained. A first randomised study of 67 patients showed a decrease in insufflation pressure for the deepest neuromuscular blockades. The results remain difficult to interpret as the authors compared two levels of deep blockade by monitoring the corrugator supercilii but without a group under moderate blockade, i.e. 1 to 2 TOF responses at the adductor pollicis [100]. In another prospective study including 61 patients, the intra-abdominal pressures required to ensure satisfactory surgical conditions during colorectal surgery were significantly lower in the deep neuromuscular blockade group (9 mmHg) than in the moderate blockade group (12 mmHg, P < 0.001) [101]. The third prospective study involved 62 patients undergoing cholecystectomy with an initial insufflation pressure of 8 mmHg. The results showed that insufflation pressure needed to be increased to 12 mmHg in 34% of cases in the moderate neuromuscular blockade group versus 12% in the deep blockade group (P < 0.05) [102]. A recent open prospective study showed that the deep neuromuscular blockade allowed a 25% reduction in

intra-abdominal pressure compared to an absence of neuromuscular blockade [105].

## Question 6: Is intraoperative monitoring of neuromuscular blockade necessary?

PICO. P = "adult patients receiving muscle relaxants to allow a scheduled surgical procedure", I = "intraoperative muscle relaxant injection; neuromuscular blockade monitoring", C = "no monitoring", O = "level of neuromuscular blockade"

**R6.1** – Monitoring of neuromuscular blockade intraoperatively is recommended.

(GRADE 1+) STRONG AGREEMENT

**R6.2** – The use of train-of-four stimulation of the ulnar nerve at the adductor pollicis is probably recommended to monitor intraoperative neuromuscular blockade.

(GRADE 2+) STRONG AGREEMENT

## Rationale

The SFAR recommends intraoperative monitoring of neuromuscular blockade throughout anaesthesia when a muscle relaxant is administered. This recommendation applies both in the operating theatre and the post-anaesthesia care unit. Monitoring the neuromuscular blockade with a nerve stimulator is more accurate than clinical assessment [106]. It is recommended to stimulate the ulnar nerve on the wrist with a visual or tactile evaluation of contraction of the adductor pollicis, given the ease of access and the possibility of quantifying the response in this muscle [107]. The gold standard for intraoperative stimulation remains the evaluation of the adductor pollicis response to train-of-four (TOF) stimulation at the ulnar nerve. The presence of one to two responses after TOF stimulation at the adductor pollicis indicates recovery of about 10% of initial muscle strength [106]. When a deep neuromuscular blockade of the body's most resistant muscles is indicated (diaphragm, abdominal wall muscles), it is recommended to wait until the four responses to TOF stimulation at the adductor pollicis have disappeared and to monitor via post-tetanic count (PTC) stimulation [98,108]. In this case, the presence of one or two responses at the adductor pollicis indicates complete paralysis of the abdominal muscles [108]. TOF stimulation of the facial nerve and visual evaluation of response in the corrugator supercilii offers an alternative to PTC. The neuromuscular blockade profile of the corrugator supercilii is comparable to that of more resistant muscles such as the laryngeal adductor muscles and the diaphragm. Monitoring the orbicularis oculi after stimulation of the facial nerve provides information comparable to that obtained with the adductor pollicis [87]. This may be useful in the absence of intraoperative access to the upper limbs. At the end of the procedure, it is recommended to switch over to adductor pollicis monitoring as soon as possible to quantify recovery [109]. Instrumental acceleromyographic monitoring of the adductor pollicis is more accurate than simple visual or tactile evaluation of muscle contractions [107].

## Question 7: What are the strategies for diagnosing and treating residual neuromuscular blockade?

PICO. For question 7.1, P = "adult patients receiving muscle relaxants", I = "muscle relaxants", C = "clinical test for residual neuromuscular blockade, neuromuscular blockade monitoring or absence thereof, muscle sensitivity to neuromuscular blockade",
O = "for residual neuromuscular blockade: frequency, complications related to residual neuromuscular blockade." For questions 7.2 to 7.7, P = "adult patients receiving muscle relaxants", I = "neostigmine, sugammadex", C = "reversal agent or not," O = "quantitative monitoring of neuromuscular blockade, recovery from neuromuscular blockade."

**R7.1** – The use of quantitative adductor pollicis monitoring of the neuromuscular blockade is probably recommended for diagnosing a residual neuromuscular blockade and obtaining a ratio of ≥ 0.9 for the fourth to first TOF response (T4/T1 ratio) at the adductor pollicis to eliminate the possibility of diagnosing a residual neuromuscular blockade.

(GRADE 2+) STRONG AGREEMENT

## Rationale

No clinical test is sensitive enough to detect a residual neuromuscular blockade [110]. Qualitative measurement of the ratio between the fourth and first TOF response (T4/T1) of ≥ 0.9 is required to eliminate a diagnosis of residual neuromuscular blockade [111]. Not all muscles are equally sensitive to the effects of muscle relaxants. Monitoring should be carried out on a muscle with high sensitivity to muscle relaxants and slow recovery kinetics. The adductor pollicis meets this profile and is recommended [109]. Only quantitative instrumental monitoring using the T4/T1 ratio measurement at the adductor pollicis with supramaximal stimulation of the ulnar nerve can be used to assess residual neuromuscular blockade [112,113]. The consequences of a residual neuromuscular blockade and the absence of reversal are higher morbidity and mortality within the first twenty-four hours postoperatively [114], a greater risk of critical respiratory events in the recovery room [115,116], a greater risk of postoperative pneumonia [117,118], a greater risk of pharyngeal muscle dysfunction [119], and delayed discharge from the recovery room [120].

**R7.2** – After administering a non-depolarising muscle relaxant it is recommended to await spontaneous reversal equal to four muscle responses at the adductor pollicis following TOF stimulation of the ulnar nerve before administering neostigmine.

(GRADE 1+) STRONG AGREEMENT

## Rationale

Since neostigmine is a reversible acetylcholinesterase inhibitor, it induces an increase in acetylcholine concentration in the synaptic cleft. Thus, by the law of mass action, non-depolarising muscle relaxants, which are post-synaptic nicotinic acetylcholine receptor antagonists, can unbind from these receptors if two conditions are met:

* the acetylcholine concentration is sufficiently high;

* the concentration of non-depolarising muscle relaxants is sufficiently reduced.

Since the concentration of non-depolarising muscle relaxants is responsible for the degree of neuromuscular blockade, it must have spontaneously reached a certain value to allow the neostigmine to induce an effective reversal, i.e. with a TOF ratio ≥ 0.9.

The degree of optimal neuromuscular blockade prior to neostigmine administration was determined in two studies. In the first prospective, randomised study [121], sixty-three patients were divided into four groups based on the number of tactile responses of the adductor pollicis to TOF stimulation prior to

administration of neostigmine 70 µg/kg, i.e. one, two, three or four responses. The neuromuscular blockade was induced by cisatracurium. The time taken to achieve a TOF ratio of 0.9 was (minutes, median and ranges) 22.2 (13.9-44.0), 20.2 (6.5-70.5), 17.1 (8.3-46.2) and 16.5 (6.5-143.3) when neostigmine was administered at one, two, three and four responses at the adductor pollicis respectively (not significant). Twenty minutes after neostigmine administration, a TOF ratio of 0.9 was obtained in five out of fourteen patients in Group 1, six out of sixteen patients in Group 2, ten out of sixteen patients in Group 3, and eleven out of fifteen patients in Group 4.

Therefore, the degree of blockade prior to reversal by neostigmine must have spontaneously recovered at least four visual or tactile TOF responses. The second study, of similar methodology, analysed the time it took to obtain a TOF ratio of > 0.9 after rocuronium had been administered [122]. A hundred and sixty patients were divided into eight groups of twenty according to the number of TOF responses at the adductor pollicis (one, two, three and four responses) and according to the anaesthesia maintenance agent (propofol or sevoflurane). Neostigmine was administered at a dose of 70 µg/kg. The time taken to achieve a TOF ratio > 0.9 in the propofol groups (minutes, median and range) was 8.6 (4.7-18.9), 7.5 (3.4-11.2), 5.4 (1.6-8.6) and 4.7 (1.3-7.2) in Groups 1, 2, 3 and 4, respectively (P < 0.05 between Group 4 and Groups 1 and 2). In the sevoflurane groups, this time was 26.6 (8.8-75.8), 22.6 (8.3-57.4), 15.6 (7.3-43.9) and 9.7 (5.1-26.4) in Groups 1, 2, 3 and 4 (P < 0.05 between Groups 4 and Groups 1 and 2). Recovery times were significantly shorter when anaesthesia was maintained by propofol when compared with sevoflurane (P < 0.0001). Ten minutes after administration of neostigmine when four responses at the TOF were obtained, all patients anaesthetised with propofol had a TOF ratio > 0.9 whereas only 11/20 patients (55%) in whom anaesthesia was maintained with sevoflurane. Thus, during maintenance of anaesthesia with propofol, neostigmine 70 µg/kg administered after four tactile adductor pollicis responses to TOF stimulation caused a complete reversal in less than ten minutes. On the other hand, under sevoflurane anaesthesia, reversal was not complete within ten minutes in all patients. All these results suggest that four responses to TOF, corresponding to a measured TOF ratio of ≥ 0.2, is the minimum to obtain before administering neostigmine.

**R7.3** – It is recommended to administer neostigmine with neuromuscular blockade monitoring at the adductor pollicis, at a dose between 40 and 50 µg/kg adapted to ideal body weight, but not to increase the dose beyond this level, and not to administer it in the absence of residual blockade (Fig. 1).

(GRADE 1+) STRONG AGREEMENT

## Rationale

The dose-response relationship of neostigmine administered during a deep blockade, defined by a T1/T0 ratio of 0.01, and during a more moderate blockade, defined by a T1/T0 ratio of 0.1, was established after a neuromuscular blockade by atracurium (T1 is the value of the contraction of the first response to TOF and T0 the value of the first response to TOF before the neuromuscular blockade) [123]. The dose of neostigmine required to obtain a TOF ratio > 0.7, 10 minutes after reversal at T1/T0 = 0.1 (moderate blockade) was 50 ± 7 µg/kg (mean ± SD) and 49 ± 6 µg/kg at T1/T0 = 0.01 (deep blockade) (not significant). It thus appears that, under the study conditions, the dose of neostigmine was in the range of 40 to 50 µg/kg. These results were confirmed when rocuronium was administered [124].
*Is there any point in increasing the dose of neostigmine?*

Three doses of neostigmine (20, 40 and 80 µg/kg) were administered after randomisation in twenty-seven adult patients when the atracurium-induced blockade had spontaneously returned to a T1/T0 ratio value of between 0.05 and 0.1 [125]. The time it took to obtain a TOF ratio of > 0.7 was (minutes, median and range) 11.3 (9.3-15.7), 8.3 (4.1-13.3), and 5.2 (3.0-14.0) after 20, 40 and 80 µg/kg of neostigmine respectively (*P* < 0.04 between the 20 µg/kg dose and the other two doses). These results suggest that the dose of neostigmine need not be increased due to the occurrence of a ceiling effect. The respiratory effects of neostigmine administered in the absence of residual blockade were demonstrated. In ten healthy volunteers undergoing partial blockade with rocuronium, 30 µg/kg of neostigmine was administered when the TOF ratio spontaneously reached 1.0 [126]. The main objective of this study was to assess the effects of neostigmine on upper airway patency and electromyographic activity of the genioglossus (larynx dilator) muscle. The volunteers were studied four times: before neuromuscular blockade, at TOF ratio 0.5, 1.0 and after neostigmine administration. Administration of neostigmine at TOF ratio = 1.0 caused:

* a significant increase in upper airway closing pressure compared to before the neuromuscular blockade (*p* < 0.002), and when the TOF ratio was 1.0 but before injection of neostigmine (*P* < 0.02);

* a significant reduction in genioglossus electromyographic (EMG) activity in response to an increase in negative upper airway pressure reflecting impaired dilator effect of the genioglossus muscle.

However, no changes in respiratory rate, I/E ratio, tidal volume or train-of-four (TOF) ratio were observed following neostigmine injection under the study conditions. Thus, administering neostigmine after full recovery from the blockade (TOF ratio = 1.0) decreases upper airway patency and reduces laryngeal dilation capacity.

**R7.4** – In the event of a very slight residual blockade, it is probably recommended to reduce the neostigmine dose by half.

(GRADE 2+) STRONG AGREEMENT

### Rationale

More recently, the concept of reducing the neostigmine dose when the blockade is very shallow has been studied with conflicting results. The effects of three doses of neostigmine (10, 20 and 30 µg/kg) were compared with a placebo to reverse an atracurium-induced blockade when the TOF ratio spontaneously reached 0.4 or 0.6 [127]. A hundred and twenty patients were randomised into eight groups of fifteen. The primary endpoint was the time required to obtain a TOF ratio of 1.0. When the blockade was reversed with a TOF ratio of 0.4, this time was (minutes, median and range): 19 (11-30), 11 (7-15), 9 (9-13) and 6 (4-11) after 0, 10, 20 and 30 µg/kg, respectively. With a TOF ratio of 0.6 before reversal, the time was 15 (8-20), 6 (4-16), 6 (4-14) and 5 (3-7) after 0, 10, 20 and 30 µg/kg, respectively. For example, the dose of neostigmine required to obtain a TOF ratio equal to 1.0 in less than 10 minutes was 25 ± 11 µg/kg and 24 ± 13 µg/kg for neostigmine administered after the TOF ratio had reached 0.4 and 0.6, respectively. These results confirm that the neostigmine dose can be reduced to reverse a very shallow blockade.

In a recent study, three doses of neostigmine (10, 20 and 40 µg/kg) were compared to a placebo when the blockade induced by

cisatracurium or rocuronium was spontaneously reversed, reac-hing 0.5 TOF ratio (i.e. very shallow blockade) [128]. One hundred and twelve patients were included (with fifteen lost to follow-up), i.e. twelve patients per dose of neostigmine. The primary endpoint was the time from injection of neostigmine or placebo to 1.0 TOF ratio. For cisatracurium, the time to reach 1.0 TOF ratio (minutes, median and range) was 16.8 (7.8-29.5), 10.0 (5.0-14.2), 6.5 (4.5-12.6) and 4.3 (2.8-5.3) after 0, 10, 20 and 40 µg/kg of neostigmine, respectively. For rocuronium, this time was 17.5 (7.9-37.5), 6.1 (4.8-27.8), 6.6 (4.3-13.8) and 3.8 (1.5-6.5) after 0, 10, 20 and 40 µg/kg of neostigmine, respectively. Ten minutes after neostig-mine administration, the percentage of patients with 1.0 TOF ratio after cisatracurium was 15, 50, 83 and 100% (dose: 0, 10, 20 and 40 µg/kg) and after rocuronium it was 17, 64, 83 and 100% (dose: 0, 10, 20 and 40 µg/kg). These results show that it would be pointless to reduce the neostigmine dose and that the best dose therefore remains 40 µg/kg. However, administering neostigmine at doses that are too high to reverse a very slight residual blockade is not exempt from side effects on neuromuscular transmission. In a study on sixty patients, two doses of neostigmine (20 and 40 µg/kg) were administered one, two, three or four hours after injecting a single dose of vecuronium [129]. In the forty patients receiving neostigmine 40 µg/kg, the TOF ratio had increased in thirty-two patients and decreased in eight of them. These patients had received neostigmine more than two hours after vecuronium and all had a TOF ratio > 0.9 prior to reversal. The decrease in TOF ratio lasted 17.4 to 52.6 minutes. No effects were observed with the 20 µg/kg dose. Neostigmine 40 µg/kg administered whereas the vecuronium-induced blockade has spontaneously reversed (TOF ratio > 0.9) may impair neuromuscular transmission and induce TOF fade.

**R7.5** – It is recommended to pursue quantitative monitoring of neuromuscular blockade after administration of neostigmine until a TOF ratio of ≥ 0.9 has been obtained (Fig. 1).

(GRADE 1+) STRONG AGREEMENT

### Rationale

The deeper degree of the neuromuscular blockade at the time of reversal, the longer the time between neostigmine administration and complete reversal (i.e. TOF ratio ≥ 0.9). This time ranges from 10 to 30 minutes [121]. After neostigmine administration it is therefore necessary to check the degree of recovery by monitoring the neuromuscular blockade.

**R7.6** – It is recommended to adjust the dose of sugammadex according to ideal bodyweight and the intensity of neuromuscular blockade induced by rocuronium (Fig. 2).

(GRADE 1+) STRONG AGREEMENT

**R7.7** – After administering sugammadex it is probably recommended to pursue quantitative monitoring of the neuromuscular blockade to detect a possible increase in neuromuscular blockade (Fig. 2).

(GRADE 2+) STRONG AGREEMENT

### Rationale

Sugammadex is a gamma cyclodextrin capable of encapsulating steroidal neuromuscular blocking agents specifically (rocuronium and vecuronium). A single sugammadex molecule can only encapsulate one molecule of muscle relaxant. Thus, the higher
<figure><img src="image_5.png" /></figure>

SFAR

Société Française d'Anesthésie et de Réanimation

<figure><img src="image_6.png" /><figcaption>**Fig. 1.** Decision algorithm for pharmacological non-depolarising neuromuscular blocking drug reversal using neostigmine. Adapted with permission from Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology 2010;112:1013–22.</figcaption></figure>

the concentration of steroid muscle relaxant, and therefore the deeper the blockade, the greater the amount of sugammadex that must be administered to reverse the neuromuscular blockade. This simple concept is sufficient to explain the fact that the dose of sugammadex can only be determined after quantifying the neuromuscular blockade. Monitoring is therefore essential. The dose of sugammadex required for reversal was determined for four degrees of blockade:

* very moderate blockade (0.5 TOF ratio): a sugammadex dose of 0.22 mg/kg provided a TOF ratio > 0.9 in less than five minutes in 95% of patients [130];

* moderate blockade (reappearance of two or four visual or tactile adductor pollicis responses to TOF stimulation at the adductor pollicis):

* when administered on reappearance of four responses to TOF stimulation, 1.0 mg/kg sugammadex reversed a rocuronium-induced neuromuscular blockade in less than five minutes. A dose of 0.5 mg/kg was also effective but slower (ten minutes) [131],

* when administered on reappearance of two TOF responses, a sugammadex dose of at least 2.0 mg/kg reversed a rocuronium-induced blockade in less than five minutes [132,133];

* deep blockade, i.e. one to two responses to the PTC: to reverse deep rocuronium-induced blockade following a dose of 0.6 or 1.2 mg/kg in less than five minutes, a sugammadex dose of at least 4.0 mg/kg was required [134];

* very deep blockade: to reverse a very deep blockade (three and fifteen minutes after high doses of 1.0 or 1.2 mg/kg rocuronium)
<figure><img src="image_7.png" /><figcaption>**Fig. 2.** Decision algorithm for pharmacological non-depolarising neuromuscular blocking drug reversal using sugammadex. Adapted with permission from Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology 2010;112:1013-22.</figcaption></figure>

in less than five minutes, a sugammadex dose of at least 8.0 mg/kg was required [135-137].

An inadequate dose of sugammadex may be the cause of the phenomenon of recurarisation [138]. Thus, the sugammadex dose must be adjusted to the degree of blockade at the time of reversal. Monitoring remains crucial to adjust the sugammadex dose and

should be continued after sugammadex administration to identify the potential occurrence of recurarisation [138]. The efficacy of sugammadex is decreased in elderly patients [139] and patients with severe renal failure (creatinine clearance < 30 mL/min) [140], especially in the case of deep blockade reversal (one to two responses to PTC).
**Question 8: What are the indications and precautions for use of both muscle relaxants and reversal agents in special populations?**

*Patients requiring electroconvulsive therapy*

PICO. P = "adult patients receiving muscle relaxants for electroconvulsive therapy", I = "muscle relaxants (muscle relaxant type: suxamethonium, rocuronium)", C = "muscle relaxant type", O = "reduction of complications related to generalised convulsion, duration of action according to different dosages".

**R8.1** – It is probably recommended to administer a short-acting muscle relaxant for electroconvulsive therapy.
(GRADE 2+) **STRONG AGREEMENT**

Rationale

The rationale for using muscle relaxants in this setting is to
prevent the motor consequences of generalised convulsions such
as tongue biting, falls, dislocations and fractures. The specifications
are for a fast-acting muscle relaxant that produces brief muscle
relaxation during seizures. A systematic review recommends first-
line use of suxamethonium. If there are contraindications, a short-
acting non-depolarising muscle relaxant may be proposed [141]. A
neuromuscular blockade is necessary during electroconvulsive
therapy. Suxamethonium remains the gold standard as a muscle
relaxant in the vast majority of cases. If there are formal
contraindications, combined rocuronium-sugammadex has been
proposed in certain case series [142–144].

Obese patients

PICO. P = "severe obese patient", I = "muscle relaxants and reversal agents", C = "different dosages, muscle relaxants and reversal agents", O = "time to obtain complete reversal defined as T4/T1 ratio > 0.9."

**R8.2** – For severe obese patients (BMI ≥ 40 kg/m²) it is probably recommended to administer a short-acting muscle relaxant to facilitate tracheal intubation.
(GRADE 2+) **STRONG AGREEMENT**

**R8.3** – It is probably recommended to administer suxamethonium at a dose of 1.0 mg/kg based on the actual body weight of the obese patient.
(GRADE 2+) **STRONG AGREEMENT**

Rationale

Suxamethonium provides excellent intubating conditions for
obese patients when administered at a dose of 1.0 mg/kg adapted to
the patient's actual bodyweight [145]. This gives a maximum
blockade with high-quality reproducible intubating conditions.
Laryngoscope insertion without resistance is facilitated, and the
vocal cords are open and motionless. The use of suxamethonium with
appropriate dosages calculated for ideal body mass or lean body mass
may be associated with poor intubation conditions, resulting in
resistance to the introduction of the laryngoscope and movement of
the diaphragm and/or lower limbs during tracheal tube positioning.

**R8.4** – The experts suggest administration of a non-depolaris-
ing muscle relaxant at a dose based on the lean bodyweight of
the obese patient.
**EXPERT OPINION**

Rationale

Non-depolarising muscle relaxants and reversal agents are
water-soluble drugs that are distributed in lean mass and
extracellular volumes. As a result, apart from suxamethonium,
their dose should be calculated based on lean bodyweight, which is
higher in obese subjects than in subjects with a normal mass
(Janmahasatian formula) [146].

**No recommendation** - There are insufficient data for any recommendations to be made concerning the interest of a deep blockade for laparoscopic surgery in obese patients.

Rationale

In laparoscopic surgery, compared to a strategy without a
muscle relaxant, the neuromuscular blockade leads to improved
visibility within the operating field, absence of movement and
increased safety of the surgical procedure [94,105]. The depth of
blockade remains an unresolved issue. The interest of a deep
blockade defined by a PTC of one to two responses, compared to a
moderate blockade or TOF stimulation involving two responses,
has not been demonstrated as yet. Only one study reported a
reduction in intra-abdominal pressure with better operating
conditions in patients undergoing laparoscopic colectomy
[101]. Another study reported marginally better operability,
approaching significance in patients undergoing a cholecystectomy
[95]. These studies involved mostly non-obese patients. As no
studies have been performed in the obese subjects, no conclusions
can be drawn regarding the interest of a deep blockade for
laparoscopic surgery in obese patients.

**R8.5** – The use of sugammadex adjusted to ideal bodyweight in severe obese patients (BMI ≥ 40 kg/m²) is probably recommended given the increased recovery time and the risk of reappearance of the neuromuscular blockade with neostigmine.
(GRADE 2+) **STRONG AGREEMENT**

Rationale

With steroid muscle relaxants, administration of neostigmine based on actual bodyweight at a dose of 0.04 mg/kg in combination with atropine 0.02 mg/kg is associated with a longer recovery time in obese subjects compared with non-obese subjects [147]. Sugammadex allows faster reversal than neostigmine [148]. Although the marketing authorisation states that the dose of sugammadex must be adapted to actual bodyweight, reversal of a partial blockade with two responses to TOF was obtained as quickly with a dose of 2.0 mg/kg calculated on the basis of ideal body mass (height in cm minus 110 in women and height in cm minus 100 in men) plus 40% (corrected weight) [149]. In the case of a deep blockade defined by the absence of response to TOF stimulation, the dosage should be increased to 4.0 mg/kg. In this case, adjusting the dosage to ideal bodyweight leads to reversal of the neuromuscular blockade in just over four minutes [150].

Children

**R8.6** – Other than situations for which rapid-sequence induction or the use of a depolarising muscle relaxant are indicated, the use of a non-depolarising muscle relaxant is probably recommended to improve intubating conditions during anaesthesia in children by intravenous induction.
(GRADE 2+) **STRONG AGREEMENT**
## Rationale

The SFAR Consensus Conference drawn up in 1999 did not recommend the use of muscle relaxants in children, whether induction is inhaled or intravenous. In fact, in France it is common not to use a muscle relaxant in children [151], and numerous hypnotic/opioid combinations have been reported [152]. However, in the context of intravenous induction, a meta-analysis of randomised studies in children reports improved intubation conditions when muscle relaxants are used [153-160]. In addition, the doses of opioid or hypnotics that allow tracheal intubation without a muscle relaxant are high and have haemodynamic effects that cannot be overlooked [156,158,161]. These results support those of a French cohort study [162]. In reference to the December 2017 ANSM alert on suxamethonium, depolarising muscle relaxants should not be used for intravenous induction, which is not part of a rapid-sequence induction [7]. During inhaled induction, non-use of a muscle relaxant in children is a very common practice in France (92%) [151]. In this context, the duration of exposure to sevoflurane, its concentration, the agent(s) associated with the drug (opioid-propofol) affect the quality of intubating conditions but may also affect haemodynamic parameters [152,163-165]. In all cases, achieving sufficient depth of anaesthesia and obtaining apnoea are the key conditions for success with this technique [166]. However, a muscle relaxant may be used during inhaled induction, especially in infants, for whom a prospective randomised study as well as a large-scale quality assurance study noted benefits associated with the inclusion of a muscle relaxant as regards intubating conditions and respiratory events [86,167]. These data allow the use of a muscle relaxant during inhaled induction in children and militate in favour of studies evaluating circumstances in which the use of muscle relaxants might prove beneficial. These benefits must be considered in the light of low and little-known allergic risk [10,168] and of full mastery by the anaesthetist over neuromuscular blockade and reversal in children.

**R8.7** – In rapid-sequence induction, use of a rapid-onset muscle relaxant is recommended in children.

(GRADE 1+) STRONG AGREEMENT

**R8.8** – In conventional rapid-sequence induction, it is probably recommended that suxamethonium be given as a first-line drug for rapid-sequence induction in children. Where suxamethonium is contraindicated, use of rocuronium is probably recommended.

(GRADE 2+) STRONG AGREEMENT

## Rationale for 8.7 and 8.8

As in adults, it is recommended to limit the time between loss of consciousness and protection of the upper airways through intubation [169,170]. This time must be kept short since the duration of apnoea without hypoxemia is shorter in younger children [171]. Use of a muscle relaxant to improve intubation conditions, a muscle relaxant-free intubation technique or inhaled induction techniques are not recommended. Regarding fast-acting muscle relaxants, suxamethonium remains the expert choice. Age-appropriate doses of suxamethonium have been determined (< 1 month: 1.8 mg/kg, > 1 month and < 1 year: 2.0 mg/kg, > 1 year and < 10 years: 1.2 mg/kg, > 10 years: 1.0 mg/kg). Rocuronium at a dose higher than 0.9 mg/kg [172] may offer an alternative to suxamethonium, however, in 2018 sugammadex had not yet been granted marketing approval for children aged

under two. The choice between suxamethonium and rocuronium will thus be based on the desired duration of neuromuscular blockade, the anticipated difficulties of intubation, and the presence and/or risk of ignoring underlying myopathy. The muscle relaxant most often compared to suxamethonium in the literature is rocuronium due to its rapid-onset of action and the intubating conditions it offers [173]. The dosage is 0.6 to 0.9 mg/kg [172].

A retrospective cohort study identified no difference in incidence of complications between suxamethonium and non-depolarising muscle relaxants in terms of respiratory risk and difficult intubations [174]. In the latest Cochrane review, which assesses intubating conditions with rocuronium and suxamethonium, suxamethonium provides intubating conditions equivalent to or better than those obtained with rocuronium despite numerous biases in the various studies [8]. This review therefore concludes that suxamethonium should continue to be preferred (especially since its duration of action is shorter) and that rocuronium should only be used where suxamethonium is contraindicated [8,175]. Contraindications to suxamethonium include risk of malignant hyperthermia, muscle diseases with risk of rhabdomyolysis, hyperkalaemia, allergy and situations involving risk of hyperkalaemia [174]. Sugammadex has demonstrated its value in reversing the effects of rocuronium [176,177]. Indeed, a recent meta-analysis by Won et al. showed that sugammadex shortens mean time to achievement of ≥ 0.9 TOF ratio, with an extubation time comparable to neostigmine or placebo [176]. The conclusions of the studies regarding risk of anaphylaxis are contradictory. The study by Reddy et al. shows a similar risk of anaphylaxis for suxamethonium and rocuronium [13]. Reitter et al. found a higher risk with suxamethonium in the results cited in the study appendix [178]. This risk may be lower with atracurium and cisatracurium, but it is present nonetheless [13,179]. Moreover, the risk of anaphylaxis with sugammadex does not appear to be negligible [180,181].

**No recommendation** – There is insufficient data on which to base any recommendations regarding the administration of a muscle relaxant in children to facilitate face mask ventilation, the insertion of supraglottic devices and management of related complications and surgical procedures and facilitate surgery or regarding the value of neuromuscular blockade monitoring for intraoperative tracheal intubation or the diagnosis and treatment of a residual neuromuscular blockade.

## Rationale

In paediatric anaesthesia, the frequency of residual neuromuscular blockade is estimated at 28% in children receiving a muscle relaxant and monitoring is therefore warranted [182]. There are no studies evaluating the occurrence of adverse events depending on whether a reversal agent is given. Similarly, there are no studies comparing the incidence of residual neuromuscular blockade based on age or the application of a neuromuscular blockade monitoring strategy.

### Neuromuscular diseases

PICO: P = "patients with neuromuscular diseases", I = "administration of different types of muscle relaxant", C = "patients with or without neuromuscular disease", O = "degree of neuromuscular blockade, side effects, residual neuromuscular blockade, reversal agents".

**R8.9** – The use of suxamethonium is not recommended in cases of primary muscle damage (myopathies) or up-regulation of nicotinic acetylcholine receptors at the motor end plate (chronic motor deficit).

(GRADE 1–) STRONG AGREEMENT
## Rationale

Suxamethonium is contraindicated in both these situations. In specific muscle disorders (myopathy, myotonia), it induces generalised contraction with rhabdomyolysis [183]. In the event of impairment of the nicotinic acetylcholine receptors (nAChRs) at the motor end plate through up-regulation (chronic damage of motoneurons, extensive and deep burns, prolonged critical illness), suxamethonium can cause life-threatening hyperkalaemia a few days after constitution of the neurological and/or muscle lesions, and over an extended period of time [183–185].

**R8.10** – Monitoring of neuromuscular blockade is probably recommended following muscle relaxant use in patients with neuromuscular disease.

(GRADE 2+) STRONG AGREEMENT

## Rationale

In cases of down-regulation of nAChRs (myasthenia), muscle relaxants are not contraindicated but significant pharmacodynamic changes have been reported. With suxamethonium, resistance is observed (decreased potency and need to increase the dose to achieve the same effect) [186,187]. For non-depolarising muscle relaxants, there is an increase in sensitivity and in duration of action, with reduced intraoperative dose requirement. A 50–75% reduction in the recommended dose is common with atracurium and cisatracurium [188,189]. This reduction in dose requirement correlates with the severity of myasthenia. Neuromuscular blockade monitoring is recommended to avoid overdosing. Evaluation in myasthenic patients of the TOF ratio by EMG in the hypothenar hand muscles prior to muscle relaxant administration predicts sensitivity to non-depolarising muscle relaxants. If the TOF ratio is less than 0.9 before the neuromuscular blockade, sensitivity to muscle relaxants is greater and the injected doses must be lower than in myasthenic subjects with a ratio greater than 0.9 [190]. In the case of primary muscle damage, there is a very significant increase in sensitivity to rocuronium (reduced dose requirement). A comparative study showed that after a dose of 0.6 mg/kg of rocuronium, onset and recovery times were significantly longer for Duchenne muscular dystrophy patients compared to controls [191]. In cases of up-regulation of nAChRs, sensitivity to non-depolarising muscle relaxants is reduced and higher doses are required to achieve the same effect [192]. The small populations in the various studies warrant GRADE 2 classification.

**R8.11** – Administration of sugammadex is probably recommended for reversal of a residual neuromuscular blockade following the use of a steroidal muscle relaxant in patients with neuromuscular disease.

(GRADE 2+) STRONG AGREEMENT

## Rationale

The risks of residual neuromuscular blockade are increased in neuromuscular disease. In myasthenia patients, neostigmine may interfere with long-term treatment. In primary muscle damage, neostigmine and atropine are difficult to deal with due to drying of secretions (atropine), potential rhythm and conduction disorders (both), central effects (atropine), slow response and effects on muscle action potential (neostigmine). Case series have described the use of sugammadex as a reversal agent for rocuronium in patients with neuromuscular disease [193,194]. The results are comparable with those observed in clinical trials conducted in subjects without neuromuscular disease (see R-7.2) regarding efficacy and time to onset of action. The small sample sizes of patients in the different studies warrant GRADE 2 classification.

Renal/hepatic failure, elderly subjects

**R8.12** – The use of a benzylisoquinoline muscle relaxant (atracurium/cisatracurium) is probably recommended in cases of renal/hepatic failure.

(GRADE 2+) STRONG AGREEMENT

## Rationale

In this setting, the pharmacodynamics of muscle relaxants excreted by kidney or liver are modified and their elimination is delayed. This may result in extended duration of action of these agents, particularly with repeated injections or continuous infusion [195]. In addition, interindividual response variability is greater in these populations, resulting in increased difficulty in dealing with these agents. Rocuronium is mainly eliminated in urine and bile [196] and its clearance is thus reduced in renal failure patients [197] and cirrhotic patients, in whom there is wide variability in the duration of action of repeated injections [198]. The pharmacokinetics and pharmacodynamics of atracurium, roughly half of which is eliminated by organ-independent reactions (Hofmann reaction and ester hydrolysis) and half by metabolism or excretion [199], are similar in subjects with and without kidney and liver failure [200,201]. On the other hand, its active metabolite, laudanosine, accumulates in patients in renal failure but does not reach concentrations causing adverse effects, even after infusion for up to 72 hours [202]. Cisatracurium, one of the ten isomers of atracurium, elimination of which is overwhelmingly non-enzymatic [203], also has similar pharmacokinetic and pharmacodynamic profiles in patients with and without renal and hepatic failure [204]. Since this agent is more potent than atracurium, the doses, and hence the amounts of laudanosine generated, are significantly lower.

**R8.13** – It is recommended not to modify the initial dose in renal/hepatic failure patients, irrespective of the type of muscle relaxant used.

(GRADE 1+) STRONG AGREEMENT

## Rationale

While the duration of action of a single dose of rocuronium is extended in renal failure patients and in the elderly, the time to onset of action remains unchanged [205]. In cirrhotic patients, the efficacy of the initial dose of rocuronium is reduced since the increase in distribution volume results in a lower concentration [198]. However, this effect is particularly remarkable at low doses and is no longer clinically noticeable at intubation doses [198]. The same is true of atracurium [206] and cisatracurium [207] in renal/hepatic failure. Consequently, to ensure effective concentrations of muscle relaxants during intubation, it is necessary and sufficient to administer the usual dose in both renal and hepatic failure patients and cirrhotic patients.

**R8.14** – When using sugammadex in cases of renal failure, it is probably recommended to administer it at the usual dose.

(GRADE 2+) STRONG AGREEMENT

## Rationale

Sugammadex is eliminated in urine and thus accumulates in renal failure patients [197]. However, clinical studies have shown
that the efficacy of sugammadex is maintained in renal failure patients at the same doses as in subjects with normal renal function, without any signs of recurarisation [208]. Sugammadex may be removed by dialysis, as may sugammadex-rocuronium complex [209].

**No recommendation** - There is insufficient data in the literature to establish a recommendation concerning the use of muscle relaxants in the elderly.

## Disclosure of interest

Christophe Baillard, Bertrand Debaene, Thomas Fuchs-Buder, Gilles Lebuffe, Benoît Plaud, Claude Meistelman, Julien Raft, Karem Slim, Didier Sirieux report personal fees from Merck Sharp & Dohme™ France.

Jean-Louis Bourgain, Gaëlle Bouroche, Laetitia Desplanque, Jean-Michel Devys, Dominique Fletcher, Cyrus Motamed, Frédérique Servin, Lionel Velly, Franck Verdonk declare that they have no competing interest.

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