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Neuromuscular blocking agents

Resistance towards nondepolarising muscle relaxants

prolonged onset time

A systematic review

Mørk, Emilie L.; Kristensen, Mette L.; Stokholm, Janne B.; Söderström, Carl M.; Madsen, Matias V.; Gätke, Mona R.

Author Information
European Journal of Anaesthesiology: July 2019 - Volume 36 - Issue 7 - p 477-485
doi: 10.1097/EJA.0000000000000991

Abstract

Introduction

Nondepolarising muscle relaxants (NDMRs) provide optimal conditions for facilitating tracheal intubation,1 improve muscle relaxation during surgery2 and aid mechanical ventilation in critically ill patients.3

The response to NDMRs is predictable in most patients. The effective dose to obtain complete muscle paralysis is normally two to three times the ED95 (the dose that on average causes 95% suppression of neuromuscular response). However, an altered response to NDMRs is seen in different clinical conditions, diseases, and pharmacological interactions, resulting in resistance to NDMRs and causing unpredicted prolongation of the onset time of neuromuscular blockade (NMB). In the peri-operative setting, an unexpected insufficient level of NMB from a bolus dose that would normally cause paralysis may result in difficult tracheal intubation or sudden muscle contractions during surgery. For instance, in patients with Duchenne muscular dystrophy (DMD), time to full muscle paralysis following rocuronium 0.6 mg kg−1 is approximately 200 s compared with 90 s in the normal surgical population.4 It is therefore important to be aware of the factors causing prolonged onset time to prevent unexpected insufficient muscle relaxation, as this may impair patient safety. Hence, the aim of this systematic review was to evaluate current evidence to elucidate clinical conditions, diseases and pharmacological interactions that cause resistance, and thereby clarify which patient groups are at risk of a having a clinically relevant prolonged onset time of a NDMR.

Materials and methods

Systematic literature search

A comprehensive search strategy was developed to identify all literature relevant to our study question, defined as a prolonged onset time in cases compared with healthy controls. PubMed and EMBASE were searched using the terms ‘onset’, ‘resistance’, ‘hyposensitivity’ and ‘unparalysed’ in combination with the included NDMR (Table 1). The initial systematic literature search was conducted in May 2015. Updated and revised final searches were conducted in April 2016 (Supplementary Appendix S1, https://links.lww.com/EJA/A199). In addition, reference lists of included records were screened to find otherwise missed studies. After 1 March 2017, no new records were added.

T1-2
Table 1:
PICOS framework (Population, Intervention, Controls, Outcome and Study design)

Inclusion criteria

We designed a PICOS framework (Population, Intervention, Controls, Outcome, Study design) to identify relevant references (Table 1). Also, at least one study within each category (clinical condition, disease, and pharmacological interaction) had to show a difference in onset time that exceeded 25% in cases compared with controls, as this was considered to be the minimal clinically relevant difference in onset time.

Exclusion criteria

We excluded expert opinions, case reports, animal studies and studies in languages other than English, French, German, Danish, Swedish and Norwegian. In addition, studies evaluating resistance towards a NDMR due to age and sex were excluded.

Study selection

The result from the search strategy was imported into the programme Covidence (www.covidence.org). Double hits were removed, and all records were individually screened for eligibility by two authors. Records that did not meet the inclusion criteria, based on title and abstract, were excluded. The remaining references were evaluated in full text for eligibility by two authors. Records that did not fulfil our PICOS framework were excluded. A flowchart of the literature search was made to illustrate a description of included and excluded articles, and the reason for exclusion (Fig. 1).

F1-2
Fig. 1:
PRISMA flow diagram. Results from structured literature search in PubMed and EMBASE.

Data extraction

For all included papers, the full manuscript was thoroughly reviewed independently by two authors, and data were extracted using specific data extraction sheets (Supplementary Appendix S2, https://links.lww.com/EJA/A199). Only the PICOS-defined outcomes were considered to be relevant for further analysis.

Reporting of results and statistical analysis

Results were reported according to the PRISMA recommendations for reporting of systematic reviews.5 The degree of resistance towards NDMRs was reported comparing onset time in cases and controls. Onset time T15 (Time between administration of NDMR until 95% depression of baseline twitch height of the first twitch in a Train-of-four stimuli) was preferred, as this is the definition of onset time according to ‘Good Clinical Practice’ in pharmacodynamic studies of neuromuscular blocking agents.6 Some studies evaluated more than one type of onset time. If onset time T15 was not evaluated, T110 (time to 90% depression) was preferred, then T10 (time to 100% depression) and finally T1max (time to maximal depression). Differences between cases and controls were reported as a difference in percentage and seconds comparing the mean or median. By using Student's t-test, a 95% confidence interval of the difference was calculated. Results, including quality assessment, were customised into text assessment tables according to disease, clinical condition or specific pharmacological interaction (Supplementary Appendix S3-S10, https://links.lww.com/EJA/A199). Final level of evidence was summarised for each NDMR within the different categories as summarised in Table 2 and based on studies of high quality or acceptable quality. When summarising level of evidence, a positive association was defined as a reported significant prolonged onset time (P < 0.05) in cases compared with controls including a difference in onset time (ΔOnset-time) of at least 25%. A summary of the final level of evidence within each category given a specific NDMR is shown in Table 3.

T2-2
Table 2:
Criteria for each level of evidence
T3-2
Table 3:
Summary of final level of evidence given to each of the included studies (shown by reference number)

Assessment of bias

Assessment of internal validity was evaluated using the Scottish Intercollegiate Guidelines Network (SIGN) Handbook (Table 4).7 For each article, two authors critically appraised the evidence by assessing the presence of selection bias, information bias and confounding. This was done using specific checklists for cohort studies and randomised controlled trials (RCTs), using only components applicable to our study question.8 The modified checklist for cohort studies included 11 statements and the checklist for RCTs included 10 statements that could be answered with a ‘yes’, ‘no’ or ‘does not apply’. One point was given if it was answered with a yes. For a cohort study, 1 to 5 points were rated as ‘low quality’ (2-), 6 to 8 points were rated as ‘acceptable quality’ (2+) and 9 to 11 points were rated as ‘high quality’ (2++). For RCTs, 1 to 4 points were rated as ‘low quality’ (1-), 5 to 7 points were rated as ‘acceptable quality’ (1+) and 8 to 10 points were rated as ‘high quality’ (1++). For an RCT to be rated higher than a low-quality study, three statements regarding blinding and randomisation were obliged to be answered with a yes. Checklists were compared, and any disagreements were resolved by consensus or by involving a senior reviewer. Each individual article was then allocated a level of evidence based on the type of study and the overall presence or absence of bias (Table 4). Due to the inability to confirm or deny a possible correlation in low-quality studies, studies rated as 1- or 2- were subsequently excluded from further analysis (Supplementary appendix S11, https://links.lww.com/EJA/A199).

T4-2
Table 4:
SIGN levels of evidence

Results

The database search identified 4455 records (Fig. 1) (Supplementary Appendix S1, https://links.lww.com/EJA/A199). After removal of double hits, 3783 titles and abstracts were screened for eligibility and 114 studies were assessed for full-text eligibility, of which 32 studies were initially included. Another 12 studies were identified from other sources.

Seven RCTs were initially included in this review, of which none were evaluated to be of high quality (1++). Two studies were evaluated to be of acceptable quality (1+).9,10 The remaining five studies were allocated as low-quality studies (1-) and were not included for further analysis, as they had a high risk of bias based on absent description of randomisation,11–14 no description of concealment of allocation11–15 and no description of blinding.14

A total of 37 prospective cohort studies were initially included in this review. Eighteen studies16–33 were classified as acceptable quality studies (2+). In these studies, only minor problems with internal validity were present and the results were evaluated as being unlikely to alter. Finally, only five studies, comprising thermal injury34–36 and DMD,4,37 were allocated as high-quality studies (2++) with a very low risk of bias. Fourteen studies were classified as low-quality studies (2-) and subsequently excluded from further analysis.38–51 The main reasons for using this classification were due to an insufficient match between cases and controls and poor descriptions of limitations and potential confounders. Furthermore, the absence of exclusion criteria led to uncertainty as to whether controls could have an altered onset time from a NDMR.

After removal of studies rated as low quality, a total of 25 studies were partitioned into one of three categories (the clinical condition, disease, or pharmacological interaction) that was believed to be the cause of resistance (Table 3).

Clinical conditions

Thermal injury

Six cohort studies22,23,25,34–36 evaluated onset time in patients with thermal injury (Table 3) (Supplementary Appendix S3, https://links.lww.com/EJA/A199). ΔOnset-time was prolonged for rocuronium by 35 to 170% (15 to 75 s)34,35 and vecuronium by approximately 95% (91 s).22 In adults given mivacurium, ΔOnset-time was prolonged by 25% (20 s),36 whereas paediatric patients given mivacurium had a similar or faster onset time.23,25

In summary, strong evidence supports resistance towards rocuronium in patients with thermal injury.34,35 In paediatric patients, the level of evidence is moderate in support of resistance towards vecuronium.22 No evidence supports resistance towards mivacurium.23,25,36

Anaesthetic technique and temperature regulation

Two RCTs and one cohort study9,10,16 evaluated onset time in patients in whom a specific anaesthetic technique or regulation in temperature was applied (Table 5) (Supplementary Appendix S4, https://links.lww.com/EJA/A199). In the first RCT, ΔOnset-time from rocuronium during induction of anaesthesia was prolonged by approximately 45% (40 s) if it was administered after infusion of remifentanil, compared with vice versa.9 In the second RCT, ΔOnset-time was prolonged by approximately 30% (23 s) in patients who were pre-operatively rehydrated with intravenous 0.9% saline compared with controls who were fasting from all fluids until 6 h before anaesthesia.10 In the cohort study, wherein one arm of each of the patients was cooled down to 27°C, ΔOnset-time from vecuronium was prolonged approximately 30% (40 s) in the cooled arm compared with the contralateral normothermic arm.16

In summary, moderate evidence supports a prolonged onset time when patients were given remifentanil prior to rocuronium,9 when patients given rocuronium were intravenously rehydrated after fasting compared with no rehydration before induction of anaesthesia10 and when patients with hypothermia of 27°C were given vecuronium.16

Diseases

Mediastinal infection

One cohort study20 evaluated onset time in patients with purulent mediastinal infection (Table 3) (Supplementary Appendix S5, https://links.lww.com/EJA/A199). ΔOnset-time from atracurium was prolonged by approximately 60% (120 s). Thus, moderate evidence supports a prolonged onset time of atracurium in patients with mediastinal infection.

Neurological and neuromuscular diseases

Seven cohort studies4,21,27,30–32,37 evaluated onset time in patients with neurological or neuromuscular diseases (Table 3) (Supplementary Appendix S6, https://links.lww.com/EJA/A199). In paediatric patients with cerebral palsy, ΔOnset-time from rocuronium was prolonged by approximately 40% (35 s),21 regardless of treatment with anticonvulsants or not. In patients with DMD, ΔOnset-time from rocuronium was prolonged by 60 to 125% (113 to 132 s).4,32,37 For mivacurium, results were inconclusive, as one study found a prolonged ΔOnset-time in adolescent DMD patients of 60% (90 s),31 whereas another study indicated a nearly normal response when children and adolescent patients were pooled into one group.30 In patients with oculopharyngeal muscular dystrophy (OPMD), ΔOnset-time from cisatracurium was prolonged by almost 30% (60 s).27

In summary, there is strong evidence to support a prolonged ΔOnset-time for rocuronium in patients with DMD.4,32,37 For patients with DMD given mivacurium, the evidence is inconclusive.30,31 Moderate evidence supports a prolonged ΔOnset-time for cisatracurium in patients with OPMD.27 In paediatric patients with cerebral palsy, no evidence supports a prolonged ΔOnset-time for vecuronium, as no positive association was found.21

Congenital heart disease

One study evaluated onset time in patients with ventricular septal defects (VSDs) and atrial septal defect (ASD) given cisatracurium (Table 3) (Supplementary Appendix S7, https://links.lww.com/EJA/A199).33 In patients with VSD or ASD, ΔOnset-time was prolonged by approximately 125% (163 s) and 130% (167 s), respectively. In summary, there is moderate evidence to support a prolonged ΔOnset-time in patients with congenital heart diseases.

Hepatic disease

Three cohort studies17,19,26 evaluated onset time in patients with hepatic diseases such as liver cirrhosis and hepatoma (Table 3) (Supplementary Appendix S8, https://links.lww.com/EJA/A199). For rocuronium, one study indicated a prolonged ΔOnset-time of about 45% (50 s),17 whereas another study found a slightly faster ΔOnset-time.19 For vecuronium, no resistance was found in cirrhotic patients compared with control. However, ΔOnset-time was prolonged by 25% (56 s) when cirrhotic patients were given the urinary trypsin inhibitor ulinastatin prior to administration of vecuronium.26

In summary, evidence was moderate to support resistance to vecuronium in patients with liver cirrhosis treated with ulinastatin.26 No evidence was found for cirrhotic patients given vecuronium.26 In patients given rocuronium, evidence was inconclusive.17,19

Renal failure

Four cohort studies18,24,28,29 evaluated onset time in patients with end-stage renal failure (creatinine clearance <15 ml min−1) (Table 3) (Supplementary Appendix S9, https://links.lww.com/EJA/A199). In paediatric patients given rocuronium, ΔOnset-time was prolonged by about 60% (52 s).24 In adults, ΔOnset-time following rocuronium ranged from being slightly faster to being prolonged by up to approximately 20% (21 s).18,28,29 In summary, moderate evidence supports a prolonged ΔOnset-time in paediatric patients with renal disease.24 On the contrary, no evidence was found in adults.18,28,29

Pharmacological interactions

Urinary trypsin inhibitors

One study26 evaluated onset time in patients given ulinastatin prior to induction of anaesthesia (Table 3) (Supplementary Appendix S10, https://links.lww.com/EJA/A199). In a cohort study mentioned earlier, ulinastatin was given to patients with liver cirrhosis and ΔOnset-time for vecuronium was found to be prolonged by approximately 25% (56 s). Thus, moderate evidence supports a prolonged onset time after ulinastatin administration in patients with cirrhosis who receive vecuronium.

Discussion

Main findings

In this review, the main findings were that strong and moderate evidence supports a prolonged ΔOnset-time of NDMRs in patients with thermal injury, hypothermia or pre-operative rehydration, in patients with DMD, OPMD, severe infection, congenital heart disease and end-stage renal failure, and during pharmacological interactions with remifentanil, or ulinastatin treatment in patients with liver cirrhosis.

A number of reviews have been conducted regarding resistance towards NDMRs. However, these reviews have been mainly narrative, more focused on the mechanisms of the resistance52 or focused on specific diseases such as neuromuscular diseases53 or burns, trauma and critical illness.54

Clinical perspective

This systematic review focused on studies with clinical relevance such as onset time for NDMRs during tracheal intubation. We therefore decided not to include studies evaluating only pharmacokinetic parameters with outcomes such as volume of distribution, half-life or estimated ED95 and/or ED50 of NDMRs. However, this approach may have failed to provide evidence within some clinical conditions, diseases or pharmacological interactions.

Defining a clinically relevant prolonged onset time as more than 25% is a definition for debate. A change in percentage was chosen over a specific change in seconds, for example 30 s, as the different NDMRs included in this review have different onset times. Further, when administering a standard intubation dose of NDMR to healthy individuals, onset time may vary from 90 s when using rocuronium 0.6 mg kg−1 in combination with isoflurane induction55 to more than 5 min when using cisatracurium in combination with opioids for induction.56 On the basis of these differences in onset time, it seemed that a ΔOnset-time of at least 25% would be a relevant clinical outcome. As NDMRs act as an important part of providing optimal conditions for tracheal intubation, difficult airway management may be seen in case of a prolonged ΔOnset-time of 25%. However, risk factors other than level of NMB are also important predictors of difficult airway management. We aimed at ensuring that our results from this review have clinical relevance and our definition of prolonged onset time is pragmatic.

Fourteen cohort studies were allocated as low quality and therefore excluded from further analysis. Within categories such as thermal injury40 and hepatic39,41,42,44,45,48 or renal disease,38 a higher level of evidence is present. However, data regarding undernourished patients,49,50 patients with sickle cell disease,51 acquired immune deficiency,43 interactions with β-adrenoreceptor blocking drugs11,15,47 or phosphodiesterase inhibitors12,13 are of a low quality of evidence. Consequently, although a positive and plausible correlation exists, resistance towards NDMRs cannot be confirmed or denied. A number of case reports were also identified from the literature search, but due to low-quality assessment, these types of publications possess no ability to contribute to the conclusion in this review. Nevertheless, it seems possible that a prolonged onset time could be expected in patients with sepsis in the ICU,57 hemiplegia, hemiparesis or quadriplegia,58,59 hyperthermia,60 increased plasma cholinesterase activity61 and during immobilisation.62 Well conducted cohort studies or RCTs (when possible) are needed to confirm the findings in the above conditions, diseases and pharmacological interactions.

The strengths of our systematic review are its extensive search of the literature, and a thorough selection and evaluation by at least two independent researchers. Further, the conclusions in this review are based solely on studies evaluated as having acceptable or high-quality evidence.

This review included only studies in which onset time was evaluated, and we may have failed to provide evidence within all relevant patient categories. For example, no studies from ICUs were included, although a prolonged onset time is suggested. The main reason for exclusion of these studies was that their primary outcomes were defined as an infusion rate63,64 and were rarely targeted to any specific level of NMB. This made it difficult to standardise onset time and/or NDMR requirements in these patients.

With regard to language restriction, we included references in English, French, German, Norwegian, Swedish and Danish. This provides the risk of not including all relevant evidence and could potentially lead to language bias.

Although a large number of studies were retrieved regarding prolonged onset time from NDMRs, the number of studies evaluating a specific NDMR within a specific condition, disease, or pharmacological interaction was limited. This implies that, although the studies were well conducted, our conclusions are based on a limited number of patients. Further, due to this heterogeneity of included studies, we were not able to perform a meta-analysis of the results.

What causes resistance towards nondepolarising muscle relaxant?

There are several factors causing a prolonged onset time of NDMRs. In patients with thermal injury and patients with neurological diseases, there is an upregulation and increase in the number of immature acetylcholine receptors at the neuromuscular junction.65 This causes a prolonged onset time, as more NDMRs are needed to occupy the same percentage of receptors as in healthy individuals. Further, an increased metabolism of NDMR prolongs onset time. This is present in patients with fever, in whom Hofmann elimination of atracurium and cisatracurium is enhanced.66 Also, it is suggested that an increase in volume of distribution, as seen in patients with liver cirrhosis or end-stage liver failure or simply by intravenous fluid therapy, dilutes the concentration of NDMR in the blood and hence leads to a slower onset time, as less NDMR is available at the neuromuscular junction. During hypothermia, onset time is prolonged because transmission across the neuromuscular junction is decreased.67 In addition, it is suggested that hypothermia-induced vasoconstriction of the peripheral vessels prolongs onset time because perfusion of the muscles is impaired. Finally, a prolonged circulation time, as seen in patients with congenital heart defect, or patients given β-blockers or remifentanil causing a reduced cardiac output, results in a prolonged onset time.

Managing resistance towards nondepolarising muscle relaxants

Knowledge of a prolonged onset time may be acted upon in different ways. First, to identify a prolonged onset time, it is mandatory to employ objective neuromuscular monitoring at all times when a NDMR is administered. Objective neuromuscular monitoring is able to verify sufficient paralysis before an attempt at tracheal intubation. Second, an additional bolus of NDMR can be administered to ensure that more NDMR is available to occupy the acetylcholine receptors at the neuromuscular junction. Third, the observed resistance may be overcome by increasing the primary bolus dose.12 Fourth, a decision to use the most appropriate NDMR may provide a normal onset time, as resistance is not seen towards all types of NDMR for several patient groups. Finally, an option could be to omit a NDMR and increase depth of anaesthesia. However, larger doses of inhalational or intravenous anaesthetics to provide a sufficient level of muscle relaxation may cause hypotension and/or bradycardia.

Conclusion

This review presents an overview of the current evidence of diseases, conditions, and pharmacological interactions that causes a prolonged onset time in patients given NDMRs. Strong evidence supports a prolonged onset time in patients with thermal injury and DMD given rocuronium. Moderate evidence supports a prolonged onset time in children with renal failure given rocuronium, patients with OPMD given cisatracurium, patients with mediastinal infection given atracurium, patients with liver cirrhosis treated with ulinastatin given vecuronium, patients with hypothermia given vecuronium, patients with ASD and VSD given cisatracurium, patients being rehydrated after fasting prior to surgery given rocuronium and in patients to whom remifentanil was given prior to rocuronium. Due to a limited number of studies with high-quality evidence, better cohort studies and RCTs are encouraged in the future.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: none.

Conflicts of interest: none

Presentation: preliminary data from this study were presented as a poster presented at the DASAIM (Danish society of anaesthesia and intensive care medicine) Annual Meeting, 10-12 November 2016, Copenhagen.

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