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L.H. Lundstrøm
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  • Department of Anaesthesiology, Nordsjællands Hospital, Hillerød, Denmark

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L.H. Lundstrøm
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  • Department of Anaesthesiology, Nordsjællands Hospital, Hillerød, Denmark

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Email the author L.H. Lundstrøm
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C.H.V. Duez
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  • Research Center for Emergency Medicine, University of Aarhus, Aarhus, Denmark
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A.K. Nørskov
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  • Department of Anaesthesiology, Nordsjællands Hospital, Hillerød, Denmark
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C.V. Rosenstock
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  • Department of Anaesthesiology, Nordsjællands Hospital, Hillerød, Denmark
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J.L. Thomsen
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  • Department of Anaesthesiology and Intensive Care, Herlev Hospital, Herlev, Denmark
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A.M. Møller
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  • The Cochrane Anaesthesia, Critical and Emergency Care Group, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
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S. Strande
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  • Department of Anaesthesiology and Intensive Care, Gentofte Hospital, Gentofte, Denmark
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J. Wetterslev
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  • Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Fig 1

Forest plot of primary outcome ‘Difficult tracheal intubation’. Low risk of bias vs high or uncertain risk of bias. NMBA, neuromuscular blocking agents.

Fig 2

Forest plot of primary outcome ‘One or more events of upper airway discomfort or injury’. Low risk of bias vs high or uncertain risk of bias. NMBA, neuromuscular blocking agents.

Fig 3

Forest plot of secondary outcome ‘Difficult laryngoscopy’. Low risk of bias vs high or uncertain risk of bias. NMBA, neuromuscular blocking agents.

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Abstract

Cohort studies have indicated that avoidance of neuromuscular blocking agents (NMBA) is a risk factor for difficult tracheal intubation. However, the impact of avoiding NMBA on tracheal intubation, possible adverse effects, and postoperative discomfort has not been evaluated in a systematic review of randomised trials. We searched several databases for trials published until January 2017. We included randomised controlled trials comparing the effect of avoiding vs using NMBA. Two independent authors assessed risk of bias and extracted data. The risk of random errors was assessed by trial sequential analysis (TSA). We included 34 trials (3565 participants). In the four trials judged to have low risk of bias, there was an increased risk of difficult tracheal intubation with no use of NMBA [random-effects model, risk ratio (RR) 13.27, 95% confidence interval (CI) 8.19–21.49, P<0.00001, TSA-adjusted CI 1.85–95.04]. The result was confirmed when including all trials, (RR 5.00, 95% CI 3.49–7.15, P<0.00001, TSA-adjusted CI 1.20–20.77). There was a significant risk of upper airway discomfort or injury by avoiding NMBA (RR=1.37, 95% CI 1.09–1.74, P=0.008, TSA-adjusted CI 1.00–1.86). None of the trials reported mortality. Avoiding NMBA was significantly associated with difficult laryngoscopy, (RR 2.54, 95% CI 1.53–4.21, P=0.0003, TSA-adjusted CI 0.27–21.75). In a clinical context, one must balance arguments for using NMBA when performing tracheal intubation.

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  • This Cochrane review evaluates the effects of avoiding or using neuromuscular blocking agents on adverse events and difficulty in airway management.

  • The results suggest that avoidance of neuromuscular blocking agents is associated with increased difficulty in intubation, and an increased risk of upper airway injury.

  • The quality of evidence was rated as moderate to low. Large, high-quality trials are needed to examine the effects on airway injury, serious adverse events and mortality.

The use of neuromuscular blocking agents (NMBA) to facilitate tracheal intubation is a widely accepted procedure. Direct laryngoscopy stimulates the oropharynx and activates oropharyngeal reflexes. However, the use of NMBA will inhibit muscular contractions and improve conditions for tracheal intubation.x1Bowman, W.C. Neuromuscular block. Br J Pharmacol. 2006; 147: S277–S286

PubMed
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Due to adverse effects the use of NMBA may be undesirable. Both depolarising and non-depolarising NMBA may have side effect as anaphylaxis, cardiovascular effects related to histamine release or sympathomimetic properties, bronchospasm and prolonged paralysis. Depolarising NMBA may specifically cause muscle pain, increased serum potassium, malignant hyperthermia and increased intraocular pressure.x2Appiah-Ankam, J. and Hunter, J.M. Pharmacology of neuromuscular blocking drugs. Cont Educ Anaesth Crit Care Pain. 2004; 4: 2–7

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Thus, on the one hand, the use of NMBA may be associated with minor or (rare) serious adverse events (SAEs), but, on the other hand, cohort studiesx3Baillard, C., Adnet, F., Borron, S.W. et al. Tracheal intubation in routine practice with and without muscular relaxation: an observational study. Eur J Anaesthesiol. 2005; 22: 672–677

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, x4Lundstrom, L.H., Moller, A.M., Rosenstock, C., Astrup, G., Gatke, M.R., and Wetterslev, J. Avoidance of neuromuscular blocking agents may increase the risk of difficult tracheal intubation: a cohort study of 103,812 consecutive adult patients recorded in the Danish Anaesthesia Database. Br J Anaesth. 2009; 103: 283–290

Abstract | Full Text | Full Text PDF | PubMed | Scopus (67)
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have demonstrated that avoiding neuromuscular blocking drugs may be an independent risk factor for difficult and failed tracheal intubation.

Difficulties with tracheal intubation (DTI) by direct laryngoscopy can cause serious soft tissue damagex5Domino, K.B., Posner, K.L., Caplan, R.A., and Cheney, F.W. Airway injury during anesthesia: a closed claims analysis. Anesthesiology. 1999; 91: 1703–1711

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and DTI may be the principal causes of hypoxemic death and brain damage in relation to anaesthesia.x6Henderson, J.J., Popat, M.T., Latto, I.P., and Pearce, A.C. Difficult Airway Society guidelines for management of the unanticipated difficult intubation. Anaesthesia. 2004; 59: 675–694

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A review identified difficult airway management as the main cause of death and severe morbidity related to anaesthesia.x7Braz, L.G., Braz, D.G., Cruz, D.S., Fernandes, L.A., Modolo, N.S., and Braz, J.R. Mortality in anesthesia: a systematic review. Clinics (Sao Paulo). 2009; 64: 999–1006

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The risk of DTI may be reduced by choosing an induction strategy including, or avoiding, NMBA for facilitating tracheal intubation.

This is a co-publication of a Cochrane Review.x8Lundstrom, L.H., Duez, C.H., Norskov, A.K. et al. Avoidance versus use of neuromuscular blocking agents for improving conditions during tracheal intubation or direct laryngoscopy in adults and adolescents. Cochrane Database Syst Rev. 2017; 5: CD009237

PubMed
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We evaluated the effect of not using NMBA vs use of NMBA on difficulty of tracheal intubation by direct laryngoscopy. We addressed relevant clinical outcomes, conducted subgroup and sensitivity analyses, assessed the role of bias, and applied trial sequential analysis (TSA) to examine the level of evidence for this intervention.

Methods

This review follows the recommendations of the Cochrane Collaboration. It is based on our published Cochrane protocolx9Lundstrøm, L.H., Strande, S., Møller, A.M., and Wetterslev, J. Use versus avoidance of neuromuscular blocking agent for improving conditions during tracheal intubation or direct laryngoscopy in adults and adolescents (Protocol). Cochrane Database Syst Rev. 2011; 7: CD009237

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and Cochrane Review.x8Lundstrom, L.H., Duez, C.H., Norskov, A.K. et al. Avoidance versus use of neuromuscular blocking agents for improving conditions during tracheal intubation or direct laryngoscopy in adults and adolescents. Cochrane Database Syst Rev. 2017; 5: CD009237

PubMed
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We included randomised controlled trials (RCTs) of participants aged ≥14 yr who underwent surgery and (attempt of) tracheal intubation by direct laryngoscopy. The participants were randomised to avoidance of NMBA (= intervention) or use of NMBA (= control) for facilitation of tracheal intubation. We defined use of NMBA as the control as it is traditionally considered standard for tracheal intubation by direct laryngoscopy, while avoidance of NMBA was defined as the experimental intervention.

We searched the Cochrane Central Register of Controlled Trials; MEDLINE; Embase; BIOSIS; International Web of Science; Latin American Caribbean Health Sciences Literature (LILACS); the Chinese Biomedical Literature Database; advanced Google and Cumulative Index to Nursing & Allied Health Literature (CINAHL) until January 11, 2017. We used a systematic and sensitive search strategy to identify relevant RCTs with no language or date restrictions. We also searched for ongoing clinical trials and unpublished studies. As an example, the MEDLINE search strategy was: (1) exp Neuromuscular Blocking Agents/or Muscle Relaxants, Central/or (suxamethonium or rapacuronium or mivacurium or atracurium or doxacurium or cisatracurium or vecuronium or rocuronium or pancuronium or tubocurarine or gallamine or pipecuronium). ti,ab; (2) Laryngoscopy/or Intubation, Intratracheal/or (difficult adj3 (intubat* or laryngoscopy or airway)).mp. or ((Intubation adj3 (score or scale)) or (Cormack or Lehane)).mp. or ((tracheal adj3 intub*) or airway or laryngoscopy).ti; (3) 1 and 2; (4) ((randomised controlled trial or controlled clinical trial).pt. or randomised.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (animals not (humans and animals)).sh; (5) 3 and 4.

In the process of selecting trials for inclusion in the review, two authors (L.H.L. and either A.N. or C.D.) independently screened the titles and abstracts to identify eligible trials. The authors (L.H.L. and one of: A.N., C.D., C.V.R., J.T.) examined the full-text reports and extracted the data on a standardised paper form. We were not blinded to author, institution, or the publication source of trials. We resolved disagreements by discussion and any residual disagreements were resolved by a third author (J.W.). If necessary, we approached all corresponding authors of the included trials for additional information on the review's outcome measures and risk of bias components.

Primary outcomes

Secondary outcomes

We evaluated the validity and design characteristics of each trial. To draw conclusions on the overall risk of bias for an outcome it was necessary to evaluate the trials for major sources of bias, also defined as domains. We used the risk of bias table described in the Cochrane Handbook for Systematic Reviews of Interventions section 8.5x12Higgins, J.P.T. and Green, S. Cochrane Handbook for systematic reviews of interventions. Version 5.1.0 (updated March 2011). ; 2011

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as a tool for assessing risk of bias in included trials. We assessed the following risk of bias domains: allocation sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and sponsor bias. We defined the trials as having low risk of bias only if they adequately fulfilled all the above-mentioned domains. Publication bias occurs when the publication of research results depends on their nature and direction.x13Dickersin, K. The existence of publication bias and risk factors for its occurrence. JAMA. 1990; 263: 1385–1389

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We examined this by providing funnel plots (Supplementary material, Fig. S1Supplementary material, Fig. S1) in order to detect either publication bias or a difference between small and large studies (‘small study effects’), expressed by asymmetry.x14Egger, M., Davey Smith, G., Schneider, M., and Minder, C. Bias in meta-analysis detected by a simple, graphical test. Br Med J. 1997; 315: 629–634

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In some trials, the patients were randomised to multiple intervention and control groups or both (more than two groups, as in dose-finding studies). We combined all relevant experimental intervention groups of the trials into a single intervention group, and combined all relevant control groups into a single control group.x12Higgins, J.P.T. and Green, S. Cochrane Handbook for systematic reviews of interventions. Version 5.1.0 (updated March 2011). ; 2011

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Statistical analysis

We used Review Manager (RevMan) [Computer program]. Version 5.3.5 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014 for statistical analysis. Most often, a dichotomous outcome measure was used to assess whether an intubation was difficult or not. We reported all dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI). For mortality, which we expected to be a rare outcome, we calculated the Peto odds ratio. We used Dx2Appiah-Ankam, J. and Hunter, J.M. Pharmacology of neuromuscular blocking drugs. Cont Educ Anaesth Crit Care Pain. 2004; 4: 2–7

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, x15Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009; 9: 86

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and the Ix2Appiah-Ankam, J. and Hunter, J.M. Pharmacology of neuromuscular blocking drugs. Cont Educ Anaesth Crit Care Pain. 2004; 4: 2–7

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statistic to describe heterogeneity among the included trials.x16Higgins, J.P. and Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21: 1539–1558

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We used both a random effects model and a fixed effect model. In case of discrepancy between the two models, we report both results; otherwise, we report the random effects model.

We performed the following subgroup analyses of our primary outcomes: (1) comparison of the subgroups using depolarising with non-depolarising NMBA; (2) comparison of the subgroups with or without remifentanil or alfentanil; (3) comparison of the subgroups with or without local anaesthetic drug; (4) comparing the subgroups of trials using anticipation of a difficult airway as an inclusion criterion with those that did not use difficult airway as an inclusion criterion. If analyses of various subgroups with a binary outcome were significant, we performed a test of interaction.x17Altman, D.G. and Bland, J.M. Interaction revisited: the difference between two estimates. Br Med J. 2003; 326: 219

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We considered P<0.05 to be indicative of significant interaction between no use of NMBA effect on DTI and the subgroup category.x12Higgins, J.P.T. and Green, S. Cochrane Handbook for systematic reviews of interventions. Version 5.1.0 (updated March 2011). ; 2011

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TSA

In a single trial, interim analysis increases the risk of type I errors. To avoid type I errors, group sequential monitoring boundariesx18Lan, K.K.G. and DeMets, D.L. Discrete sequential boundaries for clinical trials. Biometrika. 1983; 70: 659–663

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were applied to decide whether a trial could be terminated early because of a sufficiently small P-value, that is, the cumulative Z-curve crosses the monitoring boundary. Sequential monitoring boundaries can also be applied to meta-analyses, called trial sequential monitoring boundaries. In TSA, the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and helps to decide whether additional trials are needed.x19Pogue, J. and Yusuf, S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet. 1998; 351: 47–52

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, x20Pogue, J.M. and Yusuf, S. Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis. Control Clin Trial. 1997; 18: 580–593 (discussion 661–6)

Abstract | Full Text PDF | PubMed | Scopus (232)
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, x21Thorlund, K., Devereaux, P.J., Wetterslev, J. et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses?. Int J Epidemiol. 2009; 38: 276–286

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, x22Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008; 61: 64–75

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The idea in TSA is that if the cumulative Z-curve crosses a boundary, a sufficient level of evidence is reached, and no further trials may be needed. However, there is insufficient evidence to reach a conclusion if the Z-curve does not cross a boundary or does not surpass the required information size. To construct the trial sequential monitoring boundaries, the required information size is needed and will be calculated as the least number of participants needed in a well-powered single trial.x19Pogue, J. and Yusuf, S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet. 1998; 351: 47–52

Abstract | Full Text | Full Text PDF | PubMed | Scopus (282)
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, x22Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008; 61: 64–75

Abstract | Full Text | Full Text PDF | PubMed | Scopus (721)
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, x23Brok, J., Thorlund, K., Gluud, C., and Wetterslev, J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008; 61: 763–769

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We adjusted the required information size for heterogeneity with a Dx2Appiah-Ankam, J. and Hunter, J.M. Pharmacology of neuromuscular blocking drugs. Cont Educ Anaesth Crit Care Pain. 2004; 4: 2–7

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diversity adjustment factor.x15Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009; 9: 86

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We applied TSA as it prevents an increase in the risk of type I error (<5%) resulting from potential multiple updating and testing on accumulating data whenever new trial results are included in a cumulative meta-analysis,x19Pogue, J. and Yusuf, S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet. 1998; 351: 47–52

Abstract | Full Text | Full Text PDF | PubMed | Scopus (282)
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, x20Pogue, J.M. and Yusuf, S. Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis. Control Clin Trial. 1997; 18: 580–593 (discussion 661–6)

Abstract | Full Text PDF | PubMed | Scopus (232)
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and provides us with important information to estimate the level of evidence of the experimental intervention.x19Pogue, J. and Yusuf, S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet. 1998; 351: 47–52

Abstract | Full Text | Full Text PDF | PubMed | Scopus (282)
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, x20Pogue, J.M. and Yusuf, S. Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis. Control Clin Trial. 1997; 18: 580–593 (discussion 661–6)

Abstract | Full Text PDF | PubMed | Scopus (232)
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, x21Thorlund, K., Devereaux, P.J., Wetterslev, J. et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses?. Int J Epidemiol. 2009; 38: 276–286

Crossref | PubMed | Scopus (365)
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Additionally, TSA provides confidence intervals adjusted for sparse data and repetitive testing (TSA-adjusted CI) in cumulative meta-analysis and important information regarding the need for additional trials and the required information size.x15Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009; 9: 86

Crossref | PubMed | Scopus (414)
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, x22Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008; 61: 64–75

Abstract | Full Text | Full Text PDF | PubMed | Scopus (721)
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We applied trial sequential monitoring boundaries according to an information size calculated for an a priori 20% relative risk reduction of difficult or failed intubation, suggested by the trials with low-risk of bias,x15Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009; 9: 86

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, x22Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008; 61: 64–75

Abstract | Full Text | Full Text PDF | PubMed | Scopus (721)
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and an intervention effect suggested by the 95% confidence limit closest to 1 in the traditional random-effects meta-analysis.

GRADE

We used the principles of the Grades of Recommendation Assessment, Development and Evaluation (GRADE) systemx24Guyatt, G.H., Oxman, A.D., Kunz, R. et al. GRADE guidelines 6. Rating the quality of evidence—imprecision. J Clin Epidemiol. 2011; 64: 1283–1293

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, x25Guyatt, G.H., Oxman, A.D., Santesso, N. et al. GRADE guidelines: 12. Preparing summary of findings tables—binary outcomes. J Clin Epidemiol. 2013; 66: 158–172

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to assess the quality of the body of evidence associated with specific outcomes. The GRADE approach is based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The quality considers: (1) within study risk of bias (methodological quality); (2) the directness of the evidence; (3) heterogeneity of the data; (4) precision of effect estimates; and (5) risk of publication bias.

Results

Description of trials

We identified 4400 references through electronic and manual search. The search was updated January 11, 2017. After excluding duplicate reports, we screened the abstracts of 2822 references. We obtained 37 publications for full text extraction. Thirty-four RCTs met our inclusion criteriax26Alexander, R., Olufolabi, A.J., Booth, J., El-Moalem, H.E., and Glass, P.S. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia. 1999; 54: 1037–1040

Crossref | PubMed | Scopus (82)
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, x27Barclay, K., Eggers, K., and Asai, T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth. 1997; 78: 92–94

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, x28Beck, G.N., Masterson, G.R., Richards, J., and Bunting, P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia. 1993; 48: 876–880

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, x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

Crossref | PubMed | Scopus (31)
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, x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

Abstract | Full Text | Full Text PDF | PubMed | Scopus (77)
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, x31Dominici, L., Gondret, R., Dubos, S., Crevot, O., and Deligne, P. Intubation in otorhinolaryngologic surgery: propofol versus propofol–suxamethonium. Ann Fr Anesth Reanim. 1990; 9: 110–114

Crossref | PubMed | Scopus (6)
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, x32Gonzalez Obregon, M.P., Rivera Diaz, R.C., Ordonez Molina, J.E. et al. Tracheal intubation quality under remifentanil–propofol with sevoflurane compared with remifentanil–propofol with rocuronium: a randomized double-blind clinical trial. Rev Esp Anestesiol Reanim. 2010; 57: 351–356

PubMed
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, x33Gulhas, N., Topal, S., Erdogan Kayhan, G. et al. Remifentanil without muscle relaxants for intubation in microlaryngoscopy: a double blind randomised clinical trial. Eur Rev Med Pharmacol Sci. 2013; 17: 1967–1973

PubMed
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, x34Hanna, S.F., Ahmad, F., Pappas, A.L. et al. The effect of propofol/remifentanil rapid-induction technique without muscle relaxants on intraocular pressure. J Clin Anesth. 2010; 22: 437–442

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, x35Harsten, A. and Gillberg, L. Intubating conditions provided by propofol and alfentanil—acceptable, but not ideal. Acta Anaesthesiol Scand. 1997; 41: 985–987

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, x36Iamaroon, A., Pitimana-aree, S., Prechawai, C., Anusit, J., Somcharoen, K., and Chaiyaroj, O. Endotracheal intubation with thiopental/succinylcholine or sevoflurane–nitrous oxide anesthesia in adults: a comparative study. Anesth Analg. 2001; 92: 523–528

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, x37Isesele, T., Amadasun, F., and Edomwonyi, N. Comparison of intubating conditions with propofol suxamethonium versus propofol–lidocaine. J West Afr Coll Surg. 2012; 2: 51–67

PubMed
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, x38Jiao, J., Huang, S., Chen, Y., Liu, H., and Xie, Y. Comparison of intubation conditions and apnea time after anesthesia induction with propofol/remifentanil combined with or without small dose of succinylcholine. Int J Clin Exp Med. 2014; 7: 393–399

PubMed
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, x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

Crossref | PubMed
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, x40Kirkegaard-Nielsen, H., Caldwell, J.E., and Berry, P.D. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology. 1999; 91: 131–136

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, x41Kopman, A.F., Klewicka, M.M., and Neuman, G.G. Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg. 2001; 93: 954–959

Crossref | PubMed | Scopus (34)
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, x42Lieutaud, T., Billard, V., Khalaf, H., and Debaene, B. Muscle relaxation and increasing doses of propofol improve intubating conditions. Can J Anaesth. 2003; 50: 121–126

Crossref | PubMed | Scopus (38)
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, x43Lowry, D.W., Carroll, M.T., Mirakhur, R.K., Hayes, A., Hughes, D., and O'Hare, R. Comparison of sevoflurane and propofol with rocuronium for modified rapid-sequence induction of anaesthesia. Anaesthesia. 1999; 54: 247–252

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, x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

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, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

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, x46Mencke, T., Jacobs, R.M., Machmueller, S. et al. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiol. 2014; 14: 39

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, x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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, x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

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, x49Nimmo, S.M., McCann, N., Broome, I.J., and Robb, H.M. Effectiveness and sequelae of very low-dose suxamethonium for nasal intubation. Br J Anaesth. 1995; 74: 31–34

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, x50Pang, L., Zhuang, Y.Y., Dong, S., Ma, H.C., Ma, H.S., and Wang, Y.F. Intubation without muscle relaxation for suspension laryngoscopy: a randomized, controlled study. Niger J Clin Pract. 2014; 17: 456–461

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, x51Pino, R.M., Ali, H.H., Denman, W.T., Barrett, P.S., and Schwartz, A. A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. Anesthesiology. 1998; 88: 673–678

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, x52Rousseau, J.M., Lemardeley, P., Giraud, D. et al. Endotracheal intubation under propofol with or without vecuronium. Ann Fr Anesth Reanim. 1995; 14: 261–264

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, x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

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, x54Schlaich, N., Mertzlufft, F., Soltesz, S., and Fuchs-Buder, T. Remifentanil and propofol without muscle relaxants or with different doses of rocuronium for tracheal intubation in outpatient anaesthesia. Acta Anaesthesiol Scand. 2000; 44: 720–726

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, x55Sivalingam, P., Kandasamy, R., Dhakshinamoorthi, P., and Madhavan, G. Tracheal intubation without muscle relaxant—a technique using sevoflurane vital capacity induction and alfentanil. Anaesth Intensive Care. 2001; 29: 383–387

PubMed
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, x59Yazdi, B., Khalili, M., Dadashpour, N., Nasab, S.M.M., Khabiri, M., and Eraghi, M.G. The comparison of atracurium and remifentanil effect on jaw relaxation and tracheal intubation condition without muscle relaxant in patients undergoing elective surgery. Acta Med Mediterranea. 2016; 32: 1029–1032

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(Supplementary material, Fig. S1Supplementary material, Fig. S1). The included trials included 3565 participants of whom 1507 were randomised to no use of NMBA and 2058 were randomised to NMBA. Table 1Table 1 shows the characteristics of the 34 trials.

Table 1 Characteristics of included trials. Alf., alfentanil; anaest., anaesthesia; ASA, ASA physical status classification system; atracur., atracurium; cisatra., cisatracurium; DL, difficul laryngoscopy; DTI, difficult tracheal intubation; etomi., etomidate; mivacur., mivacurium; NMBA, neuromuscular blocking agent; prop., propofol; random., randomised; rapacur., rapacuronium; remi., remifentanil; rocur., rocuronium; sevo., sevoflurane; suxa., suxamentonium; thia., thiamylal; thio., thiopental; UADI, upper airway discomfort or injury; vecur., vecuronium
Study ID Drug used Study characteristics Outcomes
NMBA Opioid Hypnotic Local anest. used Dose-finding study Site Random./analysed ASA Expected DTI excluded Over-weight excluded DTI UADI DL
Alexander and colleagues (1999)26x26Alexander, R., Olufolabi, A.J., Booth, J., El-Moalem, H.E., and Glass, P.S. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia. 1999; 54: 1037–1040

Crossref | PubMed | Scopus (82)
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Suxa. Alf. or Remi. Prop. Yes UK 60/60 I–II Yes Yes
Barclay and colleagues (1997)27x27Barclay, K., Eggers, K., and Asai, T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth. 1997; 78: 92–94

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Rocur. Alf. Prop. Yes Yes UK 60/60 ns Yes Yes Yes
Beck and colleagues (1993)28x28Beck, G.N., Masterson, G.R., Richards, J., and Bunting, P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia. 1993; 48: 876–880

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Suxa. Alf. Thio. or Prop. USA 64/64 I–II Yes Yes
Bouvet and colleagues (2008)29x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

Crossref | PubMed | Scopus (31)
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Cisatra. Remi. Prop. France 130/129 I–II Yes Yes Yes Yes
Combes and colleagues (2007)30x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

Abstract | Full Text | Full Text PDF | PubMed | Scopus (77)
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Rocur. Alf. Prop. France 300/300 I–II Yes Yes Yes Yes Yes
Dominici and colleagues (1990)31x31Dominici, L., Gondret, R., Dubos, S., Crevot, O., and Deligne, P. Intubation in otorhinolaryngologic surgery: propofol versus propofol–suxamethonium. Ann Fr Anesth Reanim. 1990; 9: 110–114

Crossref | PubMed | Scopus (6)
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Suxa. Alf. Prop. Yes France 60 I–III Yes Yes
González Obregón and colleagues (2010)32x32Gonzalez Obregon, M.P., Rivera Diaz, R.C., Ordonez Molina, J.E. et al. Tracheal intubation quality under remifentanil–propofol with sevoflurane compared with remifentanil–propofol with rocuronium: a randomized double-blind clinical trial. Rev Esp Anestesiol Reanim. 2010; 57: 351–356

PubMed
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Rocur. Remi. Prop. or Sevo. Columbia 100/100 I–II Yes Yes Yes Yes
Gulhas and colleagues (2013)33x33Gulhas, N., Topal, S., Erdogan Kayhan, G. et al. Remifentanil without muscle relaxants for intubation in microlaryngoscopy: a double blind randomised clinical trial. Eur Rev Med Pharmacol Sci. 2013; 17: 1967–1973

PubMed
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Suxa. Remi. Prop. Turkey 80/80 I–II Yes Yes
Hanna and colleagues (2010)34x34Hanna, S.F., Ahmad, F., Pappas, A.L. et al. The effect of propofol/remifentanil rapid-induction technique without muscle relaxants on intraocular pressure. J Clin Anesth. 2010; 22: 437–442

Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)
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Rocur. or Suxa. Remi. Prop. Yes USA 50/47 I–II Yes Yes
Harsten and colleagues (1997)35x35Harsten, A. and Gillberg, L. Intubating conditions provided by propofol and alfentanil—acceptable, but not ideal. Acta Anaesthesiol Scand. 1997; 41: 985–987

Crossref | PubMed | Scopus (21)
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Suxa. Alf. Thio. or Prop. Sweden 80/79 I–II Yes Yes
Iamaroon and colleagues (2001)36Black Black Handbag MARINA GALANTI Handbag MARINA Handbag Handbag MARINA GALANTI GALANTI GALANTI MARINA Black dc7gOdfAx36Iamaroon, A., Pitimana-aree, S., Prechawai, C., Anusit, J., Somcharoen, K., and Chaiyaroj, O. Endotracheal intubation with thiopental/succinylcholine or sevoflurane–nitrous oxide anesthesia in adults: a comparative study. Anesth Analg. 2001; 92: 523–528

Crossref | PubMed | Scopus (16)
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Suxa. Fentanyl Thio. or Sevo. Thailand 120/120 I–II Yes Yes Yes
Isesele and colleagues (2012)37x37Isesele, T., Amadasun, F., and Edomwonyi, N. Comparison of intubating conditions with propofol suxamethonium versus propofol–lidocaine. J West Afr Coll Surg. 2012; 2: 51–67

PubMed
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Suxa. None Prop. Yes Nigeria 96/88 I–II Yes Yes
Jiao and colleagues (2014)38x38Jiao, J., Huang, S., Chen, Y., Liu, H., and Xie, Y. Comparison of intubation conditions and apnea time after anesthesia induction with propofol/remifentanil combined with or without small dose of succinylcholine. Int J Clin Exp Med. 2014; 7: 393–399

PubMed
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Suxa. Remi. Prop. China 55/55 I–II Yes Yes
Kahwaji and colleagues (1997)39x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

Crossref | PubMed
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Rapacur. Fentanyl Thio. Yes USA 181/176 I–III Yes Yes
Kirkegaard-Nielsen and colleagues (1999)40x40Kirkegaard-Nielsen, H., Caldwell, J.E., and Berry, P.D. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology. 1999; 91: 131–136

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Rocur. Fentanyl Prop. Yes USA 80/80 I–II Yes Yes
Kopman and colleagues (2001)41x41Kopman, A.F., Klewicka, M.M., and Neuman, G.G. Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg. 2001; 93: 954–959

Crossref | PubMed | Scopus (34)
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Rapacur. Alf. Prop. Yes USA 100/100 I–II Yes Yes
Lieutaud and colleagues (2003)42x42Lieutaud, T., Billard, V., Khalaf, H., and Debaene, B. Muscle relaxation and increasing doses of propofol improve intubating conditions. Can J Anaesth. 2003; 50: 121–126

Crossref | PubMed | Scopus (38)
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Atracur. Fentanyl Prop. Yes France 170/160 I–II Yes Yes
Lowry and colleagues (1999)43x43Lowry, D.W., Carroll, M.T., Mirakhur, R.K., Hayes, A., Hughes, D., and O'Hare, R. Comparison of sevoflurane and propofol with rocuronium for modified rapid-sequence induction of anaesthesia. Anaesthesia. 1999; 54: 247–252

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Rocur. Fentanyl Prop. or Sevo. Yes UK 140/140 I–II Yes Yes Yes
McNeil and colleagues (2000)44x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

Abstract | Full Text | Full Text PDF | PubMed | Scopus (53)
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Suxa. Remi. Prop. Yes UK 60/60 I–II Yes Yes Yes Yes
Mencke and colleagues (2003)45x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

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Atracur. Fentanyl Prop. Germany 80/73 I–II Yes Yes Yes Yes Yes
Mencke and colleagues (2014)46x46Mencke, T., Jacobs, R.M., Machmueller, S. et al. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiol. 2014; 14: 39

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Rocur. Remi. Prop. or Sevo. Germany 83/83 I–III Yes Yes Yes Yes Yes
Naguib and colleagues (2003)47x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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Suxa. Fentanyl Prop. Yes Saudi Arabia 200/200 I Yes Yes
Naguib and colleagues (2006)48x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

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Suxa. Fentanyl Prop. Yes Saudi Arabia 180/180 I Yes Yes
Nimmo and colleagues (1995)49x49Nimmo, S.M., McCann, N., Broome, I.J., and Robb, H.M. Effectiveness and sequelae of very low-dose suxamethonium for nasal intubation. Br J Anaesth. 1995; 74: 31–34

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Suxa. Alf. Prop. Yes USA 60/60 I–II Yes
Pang and colleagues (2014)50x50Pang, L., Zhuang, Y.Y., Dong, S., Ma, H.C., Ma, H.S., and Wang, Y.F. Intubation without muscle relaxation for suspension laryngoscopy: a randomized, controlled study. Niger J Clin Pract. 2014; 17: 456–461

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Cisatra. Remi. Prop. Yes China 40/40 I–II Yes Yes Yes Yes
Pino and colleagues (1998)51x51Pino, R.M., Ali, H.H., Denman, W.T., Barrett, P.S., and Schwartz, A. A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. Anesthesiology. 1998; 88: 673–678

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Bag Cross 'Holly Pink bag Carvela Body' Mini Mivacur. or Rocur. Fentanyl Prop. Yes USA 100/98 I–II Yes Yes Yes
Rousseau and colleagues (1995)52x52Rousseau, J.M., Lemardeley, P., Giraud, D. et al. Endotracheal intubation under propofol with or without vecuronium. Ann Fr Anesth Reanim. 1995; 14: 261–264

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Vecur. Alf. Prop. Yes France 152/152 I Yes Yes
Scheller and colleagues (1992)53x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

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Suxa. Alf. Thia. or Prop. Yes USA 75/75 I Yes Yes Yes
Schlaich and colleagues (2000)54x54Schlaich, N., Mertzlufft, F., Soltesz, S., and Fuchs-Buder, T. Remifentanil and propofol without muscle relaxants or with different doses of rocuronium for tracheal intubation in outpatient anaesthesia. Acta Anaesthesiol Scand. 2000; 44: 720–726

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Rocur. Remi. Prop. Germany 120/120 I–II Yes Yes
Sivalingam and colleagues (2001)55x55Sivalingam, P., Kandasamy, R., Dhakshinamoorthi, P., and Madhavan, G. Tracheal intubation without muscle relaxant—a technique using sevoflurane vital capacity induction and alfentanil. Anaesth Intensive Care. 2001; 29: 383–387

PubMed
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Suxa. Alf. Sevo. + N2O Yes New Zealand 100/100 I–II Yes Yes Yes
Stevens and colleagues (1997)56x56Stevens, J.B., Vescovo, M.V., Harris, K.C., Walker, S.C., and Hickey, R. Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?. Anesth Analg. 1997; 84: 1222–1226

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Suxa. Alf. Thio. or Etomi. or Prop. Yes Yes USA 140/140 I–II Yes Yes Yes Yes
Striebel and colleagues (1995)57x57Striebel, H.W., Holzl, M., Rieger, A., and Brummer, G. Endotracheal intubation with propofol and fentanyl. Anaesthesist. 1995; 44: 809–817

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Vercur. + Suxa. Fentanyl Thio. or Prop. Yes Yes Germany 100/100 I–II Yes Yes
Wong and Teoh (1996)58x58Wong, A.K. and Teoh, G.S. Intubation without muscle relaxant: an alternative technique for rapid tracheal intubation. Anaesth Intensive Care. 1996; 24: 224–230

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Suxa. Pink Carvela 'Holly Mini Bag Body' Cross bag Alf. Prop. Yes Malaysia 120/120 I–II Yes Yes
Yazdi and colleagues (2016)59x59Yazdi, B., Khalili, M., Dadashpour, N., Nasab, S.M.M., Khabiri, M., and Eraghi, M.G. The comparison of atracurium and remifentanil effect on jaw relaxation and tracheal intubation condition without muscle relaxant in patients undergoing elective surgery. Acta Med Mediterranea. 2016; 32: 1029–1032

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Atracur. Remi. Prop. Iran 66/66 I–II Yes Yes

The number of randomised participants in the individual trials ranged from 40 to 300. All 34 studies were RCTs with parallel design. There were 18 dose-finding studies comprising more interventions or control groups, or both.x26Alexander, R., Olufolabi, A.J., Booth, J., El-Moalem, H.E., and Glass, P.S. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia. 1999; 54: 1037–1040

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, x27Barclay, K., Eggers, K., and Asai, T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth. 1997; 78: 92–94

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, x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

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, x40Kirkegaard-Nielsen, H., Caldwell, J.E., and Berry, P.D. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology. 1999; 91: 131–136

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, x41Kopman, A.F., Klewicka, M.M., and Neuman, G.G. Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg. 2001; 93: 954–959

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, x42Lieutaud, T., Billard, V., Khalaf, H., and Debaene, B. Muscle relaxation and increasing doses of propofol improve intubating conditions. Can J Anaesth. 2003; 50: 121–126

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, x43Lowry, D.W., Carroll, M.T., Mirakhur, R.K., Hayes, A., Hughes, D., and O'Hare, R. Comparison of sevoflurane and propofol with rocuronium for modified rapid-sequence induction of anaesthesia. Anaesthesia. 1999; 54: 247–252

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, x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

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, x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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, x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

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| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x49Nimmo, S.M., McCann, N., Broome, I.J., and Robb, H.M. Effectiveness and sequelae of very low-dose suxamethonium for nasal intubation. Br J Anaesth. 1995; 74: 31–34

Abstract | Full Text PDF | PubMed | Scopus (19)
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, x51Pino, R.M., Ali, H.H., Denman, W.T., Barrett, P.S., and Schwartz, A. A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. Anesthesiology. 1998; 88: 673–678

Black Quilted Pocket Front Women's Backpack 4q1wqI | PubMed | Scopus (39)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

Crossref | PubMed
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x54Schlaich, N., Mertzlufft, F., Soltesz, S., and Fuchs-Buder, T. Remifentanil and propofol without muscle relaxants or with different doses of rocuronium for tracheal intubation in outpatient anaesthesia. Acta Anaesthesiol Scand. 2000; 44: 720–726

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| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x55Sivalingam, P., Kandasamy, R., Dhakshinamoorthi, P., and Madhavan, G. Tracheal intubation without muscle relaxant—a technique using sevoflurane vital capacity induction and alfentanil. Anaesth Intensive Care. 2001; 29: 383–387

PubMed
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x56Stevens, J.B., Vescovo, M.V., Harris, K.C., Walker, S.C., and Hickey, R. Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?. Anesth Analg. 1997; 84: 1222–1226

Crossref | PubMed
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, x57Striebel, H.W., Holzl, M., Rieger, A., and Brummer, G. Endotracheal intubation with propofol and fentanyl. Anaesthesist. 1995; 44: 809–817

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, x58Wong, A.K. and Teoh, G.S. Intubation without muscle relaxant: an alternative technique for rapid tracheal intubation. Anaesth Intensive Care. 1996; 24: 224–230

PubMed
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In 16 trials, intubation conditions were described by the originalx26Alexander, R., Olufolabi, A.J., Booth, J., El-Moalem, H.E., and Glass, P.S. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia. 1999; 54: 1037–1040

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, x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

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, x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

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, x34Hanna, S.F., Ahmad, F., Pappas, A.L. et al. The effect of propofol/remifentanil rapid-induction technique without muscle relaxants on intraocular pressure. J Clin Anesth. 2010; 22: 437–442

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, x38Jiao, J., Huang, S., Chen, Y., Liu, H., and Xie, Y. Comparison of intubation conditions and apnea time after anesthesia induction with propofol/remifentanil combined with or without small dose of succinylcholine. Int J Clin Exp Med. 2014; 7: 393–399

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, x40Kirkegaard-Nielsen, H., Caldwell, J.E., and Berry, P.D. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology. 1999; 91: 131–136

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, x41Kopman, A.F., Klewicka, M.M., and Neuman, G.G. Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg. 2001; 93: 'Holly Pink Bag Carvela bag Cross Mini Body' 954–959

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, x43Lowry, D.W., Carroll, M.T., Mirakhur, R.K., Hayes, A., Hughes, D., and O'Hare, R. Comparison of sevoflurane and propofol with rocuronium for modified rapid-sequence induction of anaesthesia. Anaesthesia. 1999; 54: 247–252

Crossref | PubMed | Scopus (28)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

Crossref | PubMed | Scopus (252)
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, x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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, x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

Crossref | PubMed | Scopus (44)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x54Schlaich, N., Mertzlufft, F., Soltesz, S., and Fuchs-Buder, T. Remifentanil and propofol without muscle relaxants or with different doses of rocuronium for tracheal intubation in outpatient anaesthesia. Acta Anaesthesiol Scand. 2000; 44: 720–726

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or a modifiedx27Barclay, K., Eggers, K., and Asai, T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth. 1997; 78: 92–94

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, x35Harsten, A. and Gillberg, L. Intubating conditions provided by propofol and alfentanil—acceptable, but not ideal. Acta Anaesthesiol Scand. 1997; 41: 985–987

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, x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

Crossref | PubMed
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, x46Mencke, T., Jacobs, R.M., Machmueller, S. et al. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiol. 2014; 14: 39

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version of the intubation score proposed by Viby-Mogensen and colleagues.x60Viby-Mogensen, J., Engbaek, J., Eriksson, L.I. et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand. 1996; 40: 59–74

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Laryngoscopy conditions defined by Cormack and Lehanex10Cormack, R.S. and Lehane, J. Difficult tracheal intubation in obstetrics. Anaesthesia. 1984; 39: 1105–1111

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were reported in 13 trials.x28Beck, G.N., Masterson, G.R., Richards, J., and Bunting, P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia. 1993; 48: 876–880

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, x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

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, x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

Abstract | Full Text | Full Text PDF | PubMed | Scopus (77)
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, x31Dominici, L., Gondret, R., Dubos, S., Crevot, O., and Deligne, P. Intubation in otorhinolaryngologic surgery: propofol versus propofol–suxamethonium. Ann Fr Anesth Reanim. 1990; 9: 110–114

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, x32Gonzalez Obregon, M.P., Rivera Diaz, R.C., Ordonez Molina, J.E. et al. Tracheal intubation quality under remifentanil–propofol with sevoflurane compared with remifentanil–propofol with rocuronium: a randomized double-blind clinical trial. Rev Esp Anestesiol Reanim. 2010; 57: 351–356

PubMed
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, x35Harsten, A. and Gillberg, L. Intubating conditions provided by propofol and alfentanil—acceptable, but not ideal. Acta Anaesthesiol Scand. 1997; 41: 985–987

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, x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

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, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

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, x46Mencke, T., Jacobs, R.M., Machmueller, S. et al. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiol. 2014; 14: 39

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, x50Pang, L., Zhuang, Y.Y., Dong, S., Ma, H.C., Ma, H.S., and Wang, Y.F. Intubation without muscle relaxation for suspension laryngoscopy: a randomized, controlled study. Niger J Clin Pract. 2014; 17: 456–461

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, x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

Crossref | PubMed
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x56Stevens, J.B., Vescovo, M.V., Harris, K.C., Walker, S.C., and Hickey, R. Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?. Anesth Analg. 1997; 84: 1222–1226

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, x57Striebel, H.W., Holzl, M., Rieger, A., and Brummer, G. Endotracheal intubation with propofol and fentanyl. Anaesthesist. 1995; 44: 809–817

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Events of upper airway discomfort or injury were reported in seven trials.x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684
Bag bag Carvela Mini 'Holly Body' Pink Cross

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, x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

Abstract | Full Text | Full Text PDF | PubMed | Scopus (77)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x32Gonzalez Obregon, M.P., Rivera Diaz, R.C., Ordonez Molina, J.E. et al. Tracheal intubation quality under remifentanil–propofol with sevoflurane compared with remifentanil–propofol with rocuronium: a randomized double-blind clinical trial. Rev Esp Anestesiol Reanim. 2010; 57: 351–356

PubMed
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x33Gulhas, N., Topal, S., Erdogan Kayhan, G. et al. Remifentanil without muscle relaxants for intubation in microlaryngoscopy: a double blind randomised clinical trial. Eur Rev Med Pharmacol Sci. 2013; 17: 1967–1973

PubMed
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

Crossref | PubMed | Scopus (252)
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, x46Mencke, T., Jacobs, R.M., Machmueller, S. et al. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiol. 2014; 14: 39

Crossref | PubMed | Scopus (10)
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, x55Sivalingam, P., Kandasamy, R., Dhakshinamoorthi, P., and Madhavan, G. Tracheal intubation without muscle relaxant—a technique using sevoflurane vital capacity induction and alfentanil. Anaesth Intensive Care. 2001; 29: 383–387

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In total, 19 trialsx26Alexander, R., Olufolabi, A.J., Booth, J., El-Moalem, H.E., and Glass, P.S. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia. 1999; 54: 1037–1040

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, x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

Crossref | PubMed | Scopus (31)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

Abstract | Full Text | Full Text PDF | PubMed | Scopus (77)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x31Dominici, L., Gondret, R., Dubos, S., Crevot, O., and Deligne, P. Intubation in otorhinolaryngologic surgery: propofol versus propofol–suxamethonium. Ann Fr Anesth Reanim. 1990; 9: 110–114

Crossref | PubMed | Scopus (6)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x34Hanna, S.F., Ahmad, F., Pappas, A.L. et al. The effect of propofol/remifentanil rapid-induction technique without muscle relaxants on intraocular pressure. J Clin Anesth. 2010; 22: 437–442

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, x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

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, x40Kirkegaard-Nielsen, H., Caldwell, J.E., and Berry, P.D. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology. 1999; 91: 131–136

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, x41Kopman, A.F., Klewicka, M.M., and Neuman, G.G. Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg. 2001; 93: 954–959

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, x42Lieutaud, T., Billard, V., Khalaf, H., and Debaene, B. Muscle relaxation and increasing doses of propofol improve intubating conditions. Can J Anaesth. 2003; 50: 121–126

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, x43Lowry, D.W., Carroll, M.T., Mirakhur, R.K., Hayes, A., Hughes, D., and O'Hare, R. Comparison of sevoflurane and propofol with rocuronium for modified rapid-sequence induction of anaesthesia. Anaesthesia. 1999; 54: 247–252

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, x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

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, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

Crossref | PubMed | Scopus (252)
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, x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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, x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

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, x51Pino, R.M., Ali, H.H., Denman, W.T., Barrett, P.S., and Schwartz, A. A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. Anesthesiology. 1998; 88: 673–678

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, x52Rousseau, J.M., Lemardeley, P., Giraud, D. et al. Endotracheal intubation under propofol with or without vecuronium. Ann Fr Anesth Reanim. 1995; 14: 261–264

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, x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

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, x54Schlaich, N., Mertzlufft, F., Soltesz, S., and Fuchs-Buder, T. Remifentanil and propofol without muscle relaxants or with different doses of rocuronium for tracheal intubation in outpatient anaesthesia. Acta Anaesthesiol Scand. 2000; 44: 720–726

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, x56Stevens, J.B., Vescovo, M.V., Harris, K.C., Walker, S.C., and Hickey, R. Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?. Anesth Analg. 1997; 84: 1222–1226

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reported the ‘time from induction to start of intubation’ with a median time of 90 s (range 30–270 s). In 16 of these trials the timing was equal between the intervention and the control groups. However, in two trialsx42Lieutaud, T., Billard, V., Khalaf, H., and Debaene, B. Muscle relaxation and increasing doses of propofol improve intubating conditions. Can J Anaesth. 2003; 50: 121–126

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| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

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the patient in the control group was intubated according to TOF-values/fasciculation and in one trialx52Rousseau, J.M., Lemardeley, P., Giraud, D. et al. Endotracheal intubation under propofol with or without vecuronium. Ann Fr Anesth Reanim. 1995; 14: 261–264

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the time to intubation differed between intervention and control groups (180 vs 60 s).

Risk of bias

We performed the risk of bias assessment of the trials using the previously described criteria. Four trials were judged as low risk of bias in all domains.x38Jiao, J., Huang, S., Chen, Y., Liu, H., and Xie, Y. Comparison of intubation conditions and apnea time after anesthesia induction with propofol/remifentanil combined with or without small dose of succinylcholine. Int J Clin Exp Med. 2014; 7: 393–399

PubMed
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, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

Crossref | PubMed | Scopus (252)
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, x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

Crossref | PubMed | Scopus (44)
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Table 2Table 2 reports the bias risk assessments. In our assessment of potential reporting bias, we provided funnel plots of our primary outcomes. The plots did not express asymmetry, thus not indicating publication bias (Supplementary material, Fig. S2Supplementary material, Fig. S2).

Table 2 Risk of bias summary. Review authors' judgements about each risk of bias item for each included study
Study ID Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Selective reporting
(Selection bias) (Selection bias) (Performance bias) (Detection bias) (Attrition bias) (Reporting bias)
Alexander and colleagues (1999)26x26Alexander, R., Olufolabi, A.J., Booth, J., El-Moalem, H.E., and Glass, P.S. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia. 1999; 54: 1037–1040

Crossref | PubMed | Scopus (82)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
Low Unknown Unknown Low Low Low
Barclay and colleagues (1997)27x27Barclay, K., Eggers, K., and Asai, T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth. 1997; 78: 92–94

Abstract | Full Text PDF | PubMed | MANOUKIAN amp; Black bumbag Rucksack Rucksack amp; MANOUKIAN MANOUKIAN Rucksack bumbag Black F7OrqF
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Unknown Unknown Unknown Low Low Low
Beck and colleagues (1993)28x28Beck, G.N., Masterson, G.R., Richards, J., and Bunting, P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia. 1993; 48: 876–880

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Unknown Unknown Unknown Low Low Low
Bouvet and colleagues (2008)29x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

Crossref | PubMed | Scopus (31)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
Low Low High Low Low Low
Combes and colleagues (2007)30x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

Abstract | Full Text | Full Text PDF | PubMed | Scopus (77)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
Unknown Low Low Low Low Low
Dominici and colleagues (1990)31x31Dominici, L., Gondret, R., Dubos, S., Crevot, O., and Deligne, P. Intubation in otorhinolaryngologic surgery: propofol versus propofol–suxamethonium. Ann Fr Anesth Reanim. 1990; 9: 110–114

Crossref | PubMed | Scopus (6)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
Low Unknown Unknown Low Low Low
González Obregón and colleagues (2010)32x32Gonzalez Obregon, M.P., Rivera Diaz, R.C., Ordonez Molina, J.E. et al. Tracheal intubation quality under remifentanil–propofol with sevoflurane compared with remifentanil–propofol with rocuronium: a randomized double-blind clinical trial. Rev Esp Anestesiol Reanim. 2010; 57: 351–356

PubMed
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Low Low High Low Low Low
Gulhas and colleagues (2013)33x33Gulhas, N., Topal, S., Erdogan Kayhan, G. et al. Remifentanil without muscle relaxants for intubation in microlaryngoscopy: a double blind randomised clinical trial. Eur Rev Med Pharmacol Sci. 2013; 17: 1967–1973

PubMed
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
Low Unknown Low Low Low Low
Hanna and colleagues (2010)34x34Hanna, S.F., Ahmad, F., Pappas, A.L. et al. The effect of propofol/remifentanil rapid-induction technique without muscle relaxants on intraocular pressure. J Clin Anesth. 2010; 22: 437–442

Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)
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PubMed
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Effects of interventions

See our main results on in the summary of findings table (Table 3Table 3) grading the quality of the evidence, including imprecision, according to GRADE.x24Guyatt, G.H., Oxman, A.D., Kunz, R. et al. GRADE guidelines 6. Rating the quality of evidence—imprecision. J Clin Epidemiol. 2011; 64: 1283–1293

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, x25Guyatt, G.H., Oxman, A.D., Santesso, N. et al. GRADE guidelines: 12. Preparing summary of findings tables—binary outcomes. J Clin Epidemiol. 2013; 66: 158–172

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Table 3 Summary of findings. Intervention: avoidance of NMBA; Control: use of NMBA. The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI, confidence interval; RR, risk ratio; TSA, trial sequential analysis. GRADE Working Group grades of evidence: High quality: we are very confident that the true effect lies close to that of the estimate of the effect; Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect; Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. Notes for quality of the evidence: *downgraded one level because of indirectness; downgraded two levels because of indirectness; heterogeneity and high or uncertain risk of bias; downgraded one level because of high or uncertain risk of bias; downgraded two levels because of impression and because of high or uncertain risk of bias
Outcomes Anticipated absolute effects (95% CI) Relative effect (95% CI) of avoidance vs using NMBA No. of participants (studies) Quality of the evidence (GRADE) Comments
Assumed risk (risk with ‘use of NMBA’) Corresponding risk (risk with ‘avoidance of NMBA’)
Primary outcomes
Difficult tracheal intubation: low risk of bias trials Study population RR 13.27 (8.19–21.49) 508 (four studies) ⊕⊕⊕⊝ Moderate* TSA shows that the required information size of 8195 for a 20% RRR has not been achieved, however the trial sequential monitoring boundary has been crossed and the TSA-adjusted CI for the RR is 1.85–95.04
47 per 1000 620 per 1000 (383–1000)
Difficult tracheal intubation: all trials Study population RR 5.00 (3.49–7.15) 3565 (34 studies) ⊕⊕⊝⊝ Low TSA shows that the required information size of 44 661 for a 20% RRR has not been achieved, but the trial sequential monitoring boundary has been crossed and the TSA-adjusted CI for the RR is 1.20–20.77
81 per 1000 406 per 1000 (284–597)
One or more events of upper airway discomfort or injury: low risk of bias trials Study population RR 2.74 (1.21–6.21) 73 (one study) See comments Because of only one low risk of bias trial was identified no quality of evidence assessment was performed
162 per 1000 444 per 1000 (196–1000)
One or more events of upper airway discomfort or injury: all trials Study population RR 1.37 (1.09–1.74) 846 (seven studies) ⊕⊕⊕⊝ Moderate TSA shows that the required information size of 1981 for a 20% RRR has not been achieved, but the trial sequential monitoring boundary has been crossed and the TSA-adjusted CI for the RR is 1.00–1.86
273 per 1000 374 per 1000 (298–475)
Mortality Not estimated Not estimated 0
Secondary outcomes
Difficult laryngoscopy: low risk of bias trials Study population RR 4.00 (0.47–34.20) 78 (one study) See comments Because of only one low risk of bias trial was identified no quality of evidence assessment was performed
26 per 1000 103 per 1000 (12–877)
Difficult laryngoscopy: all trials Study population RR 2.54 (1.53–4.21) 1308(13 studies) ⊕⊕⊝⊝ Low TSA shows that the required information size of 22 911 for a 20% RRR was not achieved and none of trial sequential monitoring boundaries were crossed. The TSA-adjusted CI for the RR is 0.27–21.75
33 per 1000 85 per 1000 (51–141)

Primary outcomes

Difficult tracheal intubation (Fig. 1Fig. 1, Supplementary material, Fig. S3Supplementary material, Fig. S3)

Four trialsx38Jiao, J., Huang, S., Chen, Y., Liu, H., and Xie, Y. Comparison of intubation conditions and apnea time after anesthesia induction with propofol/remifentanil combined with or without small dose of succinylcholine. Int J Clin Exp Med. 2014; 7: 393–399

PubMed
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, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

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, x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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, x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

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with 508 participants were categorised as having low risk of bias. Among 144 participants undergoing tracheal intubation without the use of NMBA a crude proportion of 56.3% (n=81; 95% CI 49.3–64.4%) had a DTI. Of the 364 participants intubated with the use of NMBA, the proportion of DTI was 4.7% (n=17; 95% CI 2.8–6.8%). In trials with an overall low risk of bias, there was a significantly increased risk of DTI with no use of NMBA [random-effects model, RR 13.27, 95% CI 8.19–21.49, P<0.00001, TSA-adjusted CI: 1.85–95.04; 508 participants; four trials, number needed to treat for an additional harmful outcome (NNTH) =1.9, I2=0%, D2=0%, GRADE=moderate]. The results were confirmed when including all trials. Here, a total of 34 trials with 3565 participants provided data on DTI. Among 1507 participants undergoing tracheal intubation without the use of NMBA, a crude proportion of 24.2% (n=365; 95% CI 22.4–26.4%) had a DTI. Of the 2058 participants intubated with the use of NMBA, the crude proportion of DTI was 8.1% (n=167; 95% CI 7.1–9.3%). Again, we found a significantly increased risk of DTI when avoiding NMBA (RR 5.00, 95% CI 3.49–7.15, P<0.00001, TSA-adjusted CI 1.20–20.77; 3565 participants, 34 trials, NNTH=6.3, I2=70%, D2=82%, GRADE=low).

Fig 1

Forest plot of primary outcome ‘Difficult tracheal intubation’. Low risk of bias vs high or uncertain risk of bias. NMBA, neuromuscular blocking agents.

Upper airway discomfort or injury (Fig. 2Fig. 2, Supplementary material, Fig. S4Supplementary material, Fig. S4)

Only one trial reporting on upper airway discomfort or injury was categorised with overall low risk of bias. When including all trials, events of upper airway discomfort or injury were described in seven trialsx29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

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, x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

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, x32Gonzalez Obregon, M.P., Rivera Diaz, R.C., Ordonez Molina, J.E. et al. Tracheal intubation quality under remifentanil–propofol with sevoflurane compared with remifentanil–propofol with rocuronium: a randomized double-blind clinical trial. Rev Esp Anestesiol Reanim. 2010; 57: 351–356

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, x33Gulhas, N., Topal, S., Erdogan Kayhan, G. et al. Remifentanil without muscle relaxants for intubation in microlaryngoscopy: a double blind randomised clinical trial. Eur Rev Med Pharmacol Sci. 2013; 17: 1967–1973

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, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

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, x46Mencke, T., Jacobs, R.M., Machmueller, S. et al. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiol. 2014; 14: 39

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, x55Sivalingam, P., Kandasamy, R., Dhakshinamoorthi, P., and Madhavan, G. Tracheal intubation without muscle relaxant—a technique using sevoflurane vital capacity induction and alfentanil. Anaesth Intensive Care. 2001; 29: 383–387

PubMed
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representing 846 participants. The crude prevalence was 33.1% (n=280; 95% CI 30.4–36.3%). Among 447 participants undergoing tracheal intubation without the use of NMBA, 38.2% (n=171; 95% CI 34.4–42.8%) had upper airway discomfort or injury. Of the 397 participants intubated using NMBA the proportion of upper airway discomfort or injury was 27.3% (n=109; 95% CI 23.5–31.7%). There was a significant risk of upper airway discomfort or injury by avoiding NMBA (random-effects model, RR=1.37, 95% CI 1.09–1.74, P=0.008, TSA-adjusted CI 1.00–1.85; 846 participants, seven trials, NNTH=9.1, I2=13%, GRADE=moderate).

Fig 2

Forest plot of primary outcome ‘One or more events of upper airway discomfort or injury’. Low risk of bias vs high or uncertain risk of bias. NMBA, neuromuscular blocking agents.

Mortality

None of the trials reported mortality.

Secondary outcomes

Difficult laryngoscopy (Fig. 3Fig. 3)

Only one trial was categorised with overall low risk of bias. Among all trials where the conditions for laryngoscopy were reported a total of 1308 participants were included. Among 740 participants undergoing tracheal intubation without the use of NMBA, a crude proportion of 7.2% (n=53; 95% CI 5.6–9.0%) had a difficult laryngoscopy. Of the 568 participants intubated using NMBA the proportion of difficult laryngoscopy was 3.3% (n=19; 95% CI 2.1–4.8%). Avoiding NMBA was significantly associated with difficult laryngoscopy, (random-effects model, RR 2.54, 95% CI 1.53–4.21, P=0.0003, TSA-adjusted CI 0.27–21.75; 1308 participants, 13 trials, NNTH=25.6, I2=0% and D2=0%, GRADE=low).

Fig 3

Forest plot of secondary outcome ‘Difficult laryngoscopy’. Low risk of bias vs high or uncertain risk of bias. NMBA, neuromuscular blocking agents.

One or more major SAEs

One study reported SAEs.x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

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A 29-yr-old man, 100 kg, ASA physical status I, experienced two of these events (tachycardia, with heart rate 85–150 beats min−1, and bronchospasm) within 30 s of administration of 2.0 mg kg−1 ORG 9487 (rapacuronium). It was followed by erythema of the arms, shoulders, and face. The bronchospasm was treated with salbutamol, and all symptoms gradually subsided.

Subgroup analyses of primary outcomes

In our subgroup analyses concerning a DTI, the use of remifentanil, alfentanil, or local anaesthesia did not change our primary findings that avoidance of NMBA was significantly associated with a DTI. However, our subgroup analyses suggest that even though the risk of DTI was increased with no use of NMBA for both using and not using local anaesthesia, the risk was significantly lesser increased when using local anaesthesia (RR=1.90 vs 6.26). Likewise, in the subgroup analysis of trials excluding participants with expected difficult intubation avoiding NMBA increase the risk of a difficult intubation (Supplementary material, Appendix 1Supplementary material, Appendix 1).

We planned to explore possible causes of heterogeneity by performing meta-regression analyses. However, because of the low degree of heterogeneity in trials with low risk of bias concerning DTI we did not perform the assessment.

Explorative outcomes

Explorative outcomes: difficult tracheal intubation: ‘a best-case scenario’

A total of 18 trials were dose-finding studies including more interventions or control groups, or both.x26Alexander, R., Olufolabi, A.J., Booth, J., El-Moalem, H.E., and Glass, P.S. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia. 1999; 54: 1037–1040

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, x27Barclay, K., Eggers, K., and Asai, T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth. 1997; 78: 92–94

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, x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

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, x40Kirkegaard-Nielsen, H., Caldwell, J.E., and Berry, P.D. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology. 1999; 91: 131–136

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, x41Kopman, A.F., Klewicka, M.M., and Neuman, G.G. Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg. 2001; 93: 954–959

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, x42Lieutaud, T., Billard, V., Khalaf, H., and Debaene, B. Muscle relaxation and increasing doses of propofol improve intubating conditions. Can J Anaesth. 2003; 50: 121–126

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, x43Lowry, D.W., Carroll, M.T., Mirakhur, R.K., Hayes, A., Hughes, D., and O'Hare, R. Comparison of sevoflurane and propofol with rocuronium for modified rapid-sequence induction of anaesthesia. Anaesthesia. 1999; 54: 247–252

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, x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

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, x47Naguib, M., Samarkandi, A., Riad, W., and Alharby, S.W. Optimal dose of succinylcholine revisited. Anesthesiology. 2003; 99: 1045–1049

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, x48Naguib, M., Samarkandi, A.H., El-Din, M.E., Abdullah, K., Khaled, M., and Alharby, S.W. The dose of succinylcholine required for excellent endotracheal intubating conditions. Anesth Analg. 2006; 102: 151–155

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, x49Nimmo, S.M., McCann, N., Broome, I.J., and Robb, H.M. Effectiveness and sequelae of very low-dose suxamethonium for nasal intubation. Br J Anaesth. 1995; 74: 31–34

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, x51Pino, R.M., Ali, H.H., Denman, W.T., Barrett, P.S., and Schwartz, A. A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. Anesthesiology. 1998; 88: 673–678

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, x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

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, x54Schlaich, N., Mertzlufft, F., Soltesz, S., and Fuchs-Buder, T. Remifentanil and propofol without muscle relaxants or with different doses of rocuronium for tracheal intubation in outpatient anaesthesia. Acta Anaesthesiol Scand. 2000; 44: 720–726

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, x55Sivalingam, P., Kandasamy, R., Dhakshinamoorthi, P., and Madhavan, G. Tracheal intubation without muscle relaxant—a technique using sevoflurane vital capacity induction and alfentanil. Anaesth Intensive Care. 2001; 29: 383–387

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, x56Stevens, J.B., Vescovo, M.V., Harris, K.C., Walker, S.C., and Hickey, R. Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?. Anesth Analg. 1997; 84: 1222–1226

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, x57Striebel, H.W., Holzl, M., Rieger, A., and Brummer, G. Endotracheal intubation with propofol and fentanyl. Anaesthesist. 1995; 44: 809–817

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, x58Wong, A.K. and Teoh, G.S. Intubation without muscle relaxant: an alternative technique for rapid tracheal intubation. Anaesth Intensive Care. 1996; 24: 224–230

PubMed
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In the attempt to estimate the appropriate level of intervention or adjuvant drugs, or both, these trials may include intervention or control groups, or both, where the participants were suboptimally anaesthetised. We therefore performed a supplementary sensitivity analysis of a ‘best-case scenario’. Here, the dose finding studies were only represented by the control and intervention group with the lowest prevalence of difficult intubation. Among 1180 participants undergoing tracheal intubation without the use of NMBA, a crude proportion of 25.0% (n=295; 95% CI 22.9–27.5%) had a DTI. Of the 1230 participants intubated with the use of NMBA, the crude proportion of DTI was 3.4% (n=42; 95% CI 2.5–4.4%). Avoidance of NMBA significantly increased the risk of a DTI with direct laryngoscopy with a risk ratio of 5.99 (95% CI 3.46–10.38; P<0.0001, NNTH=4.4, I2=57%).

Explorative outcomes: difficult tracheal intubation: excluding dose-finding studies

In our attempt to exclude comparisons of suboptimal anaesthetic dosing regimens, we performed a sensitivity analysis excluding all dose finding trials. Thus, 16 trials having one intervention group and one control group were included.x28Beck, G.N., Masterson, G.R., Richards, J., and Bunting, P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia. 1993; 48: 876–880

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, x29Bouvet, L., Stoian, A., Jacquot-Laperriere, S., Allaouchiche, B., Chassard, D., and Boselli, E. Laryngeal injuries and intubating conditions with or without muscular relaxation: an equivalence study. Can J Anaesth. 2008; 55: 674–684

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, x30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

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, x31Dominici, L., Gondret, R., Dubos, S., Crevot, O., and Deligne, P. Intubation in otorhinolaryngologic surgery: propofol versus propofol–suxamethonium. Ann Fr Anesth Reanim. 1990; 9: 110–114

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, x32Gonzalez Obregon, M.P., Rivera Diaz, R.C., Ordonez Molina, J.E. et al. Tracheal intubation quality under remifentanil–propofol with sevoflurane compared with remifentanil–propofol with rocuronium: a randomized double-blind clinical trial. Rev Esp Anestesiol Reanim. 2010; 57: 351–356

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Among 769 participants undergoing tracheal intubation without the use of NMBA, a crude proportion of 15.5% (n=119; 95% CI 13.3–18.0%) were intubated with difficulties. Of the 767 participants intubated with the use of NMBA, the crude proportion of DTI was 4.2% (n=32; 95% CI 3.0–5.6%). Avoidance of NMBA significantly increased the risk of a DTI with a risk ratio of 3.40 (95% CI 1.63–7.10; P=0.001, NNTH=8.8, I2=59%).

Explorative outcomes: difficult tracheal intubation: funding from pharmaceutical industry

We identified 10 trials that reported funding from pharmaceutical industry.x27Barclay, K., Eggers, K., and Asai, T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth. 1997; 78: 92–94

Abstract | Full Text PDF | PubMed | MANOUKIAN amp; Black bumbag Rucksack Rucksack amp; MANOUKIAN MANOUKIAN Rucksack bumbag Black F7OrqF
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, x34Hanna, S.F., Ahmad, F., Pappas, A.L. et al. The effect of propofol/remifentanil rapid-induction technique without muscle relaxants on intraocular pressure. J Clin Anesth. 2010; 22: 437–442

Abstract | Full Text | Full Text PDF | PubMed | Scopus (21)
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, x35Harsten, A. and Gillberg, L. Intubating conditions provided by propofol and alfentanil—acceptable, but not ideal. Acta Anaesthesiol Scand. 1997; 41: 985–987

Crossref | PubMed | Scopus (21)
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, x36Iamaroon, A., Pitimana-aree, S., Prechawai, C., Anusit, J., Somcharoen, K., and Chaiyaroj, O. Endotracheal intubation with thiopental/succinylcholine or sevoflurane–nitrous oxide anesthesia in adults: a comparative study. Anesth Analg. 2001; 92: 523–528

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, x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

Crossref | PubMed
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, x41Kopman, A.F., Klewicka, M.M., and Neuman, G.G. Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg. 2001; 93: 954–959

Crossref | PubMed | Scopus (34)
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, x43Lowry, D.W., Carroll, M.T., Mirakhur, R.K., Hayes, A., Hughes, D., and O'Hare, R. Comparison of sevoflurane and propofol with rocuronium for modified rapid-sequence induction of anaesthesia. Anaesthesia. 1999; 54: 247–252

Crossref | PubMed | Scopus (28)
| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x51Pino, R.M., Ali, H.H., Denman, W.T., Barrett, P.S., and Schwartz, A. A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. Anesthesiology. 1998; 88: 673–678

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| Google ScholarBlack EA7 Rucksack bumbag bumbag bumbag Rucksack EA7 Black amp; bumbag Black amp; EA7 EA7 amp; amp; Rucksack Rucksack RqYxAwx
, x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

Crossref | PubMed
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, x58Wong, A.K. and Teoh, G.S. Intubation without muscle relaxant: an alternative technique for rapid tracheal intubation. Anaesth Intensive Care. 1996; 24: 224–230

PubMed
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In our attempt to identify any potential bias caused by industrial funding we performed a sensitivity analysis comparing trials receiving industrial funding with the remaining trials. We included all trials receiving industrial funding, not distinguishing between the types of funding the studies had received. In the 10 trials reporting industrial funding, we found a significant association between avoidance of NMBA and DTI, RR 4.10 (95% CI 2.67–6.31, P=0.003, I2=64%). The remaining trials with no industrial funding also showed a significant association between avoiding NMBA and DTI, RR 5.33 (95% CI 3.16–8.98, P<0.00001, I2=68%). There was no significant subgroup difference (P=0.45).

Discussion

Our systematic review suggests that avoidance of NMBA is associated with an increased risk of both a DTI and upper airway discomfort or injury. Our TSA demonstrated firm evidence for a harmful effect in the traditional meta-analysis on the proportions of both DTI and upper airway discomfort and injury when the significance level is adjusted for repetitive testing and sparse data in a cumulative meta-analysis. In the trials describing the conditions for laryngoscopy our meta-analysis demonstrated that avoiding NMBA was associated with a difficult laryngoscopy. However, because of inadequate information size, our TSA could not demonstrate firm evidence for a harmful effect of avoiding NMBA on upper airway discomfort or injury. Mortality was unreported in all trials and only one trial reported an episode of an (S)AE related to the use of NMBA.x39Kahwaji, R., Bevan, D.R., Bikhazi, G. et al. Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg. 1997; 84: 1011–1018

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To our knowledge there is no previous systematic review including meta-analyses of trials comparing avoidance of NMBA with use of NMBA for tracheal intubation. However, a narrative reviewx61Woods, A.W. and Allam, S. Tracheal intubation without the use of neuromuscular blocking agents. Br J Anaesth. 2005; 94: 150–158

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concluded that the literature describes successful techniques to intubate the trachea without the use of neuromuscular blocking agents under general anaesthesia. Further, these authors conclude that the techniques offer a useful alternative when these drugs are either contraindicated or undesirable. Another narrative reviewx62Fotopoulou, G., Theocharis, S., Vasileiou, I., Kouskouni, E., and Xanthos, T. Management of the airway without the use of neuromuscular blocking agents: the use of remifentanil. Fundam Clin Pharmacol. 2012; 26: 72–85

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concludes that induction of anaesthesia without the use of NMBA, but in combination with remifentanil provides acceptable conditions for tracheal intubation. Both reviews include several dose-finding trials where none of the patients in the different intervention groups were administered NMBA. Thus, it was impossible to compare avoiding vs using NMBA for tracheal intubation. Based upon the findings from specific drug combinations and concentrations, the authors concluded that induction without the use of NMBA might offer (almost) perfect or good conditions for intubation.

In large observational studies and reviews on difficult airway management, the fractions of DTIs range from 2% to 7%.x63Lundstrom, L.H., Vester-Andersen, M., Moller, A.M., Charuluxananan, S., L'Hermite, J., and Wetterslev, J. Poor prognostic value of the modified Mallampati score: a meta-analysis involving 177 088 patients. Br J Anaesth. bag Body' Carvela Mini 'Holly Cross Bag Pink 2011; 107: 659–667

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, x64Norskov, A.K., Wetterslev, J., Rosenstock, C.V. et al. Effects of using the simplified airway risk index vs usual airway assessment on unanticipated difficult tracheal intubation—a cluster randomized trial with 64,273 participants. Br J Anaesth. 2016; 116: 680–689

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, x65Shiga, T., Wajima, Z., Inoue, T., and Sakamoto, A. Predicting difficult intubation in apparently normal patients: a meta-analysis of bedside screening test performance. Anesthesiology. 2005; 103: 429–437

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This agrees with our findings on the overall proportion of difficult intubation in patients who are intubated using NMBA. The crude proportion was 4.7% in trials with low risk of bias and 8.1% in all trials. However, in patients undergoing tracheal intubation without the use of NMBA the corresponding crude proportions were considerably higher: 56.3% in trials with low risk of bias and 24.2% in all trials. These latter proportions are not in accordance with experiences from everyday clinical practice and several of the trials may therefore have included suboptimal dosing regimens. We speculate that some of the dose finding trials may include intervention groups with clinically unacceptable dosing regimens that may contribute to an unrealistically increased risk of DTI. We therefore performed two post hoc sensitivity analyses. First, we evaluated a ‘best case scenario’ where the dose finding trials were represented only by the control and intervention group with the lowest incidence of difficult intubation. In our second sensitivity analysis, we excluded all dose finding trials, leaving all trials with a single intervention group and a single control group in our meta-analysis. In both sensitivity analyses, avoiding NMBA still significantly increased the risk of a DTI. Another possible explanation for the increased crude proportion of DTI in patients induced without NMBA may be that the majority of the included trials used a (modified) intubation score according to Viby-Mogensen and colleagues.x60Viby-Mogensen, J., Engbaek, J., Eriksson, L.I. et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand. 1996; 40: 59–74

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, x66Fuchs-Buder, T., Claudius, C., Skovgaard, L.T., Eriksson, L.I., Mirakhur, R.K., and Viby-Mogensen, J. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand. 2007; 51: 789–808

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This was based on information on jaw mobility, reaction to insertion of the tracheal tube and cuff inflation (diaphragmatic movement/coughing), or both. These are reasonable elements when describing the ideal conditions for intubation, though they may be affected even in successful everyday clinical airway management without ‘truly’ experiencing difficulties. Thus, good clinical research practice score may be very sensitive and enforces the difference between the ideal and a clinical acceptable intubation. The trials reporting conditions for laryngoscopy described by Cormack and Lehanex10Cormack, R.S. and Lehane, J. Difficult tracheal intubation in obstetrics. Anaesthesia. 1984; 39: 1105–1111

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report an outcome measure traditionally used in studies dealing with difficult airway management. In our assessment, the crude proportions of difficult laryngoscopy in the intervention groups may be more recognisable and in accordance with the frequency of difficulties experienced in clinical practice and reported in the literature, as 4.2% among all trials and 7.2%, in trials with low risk of bias, who were intubated without NMBA, had a difficult laryngoscopy.

One review reports on various causes for postoperative sore throat,x67El-Boghdadly, K., Bailey, C.R., and Wiles, M.D. Postoperative sore throat: a systematic review. Anaesthesia. 2016; 71: 706–717

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and tracheal intubation without the use of NMBA is stated as a potential risk factor for sore throat. Although this study is presented as a systematic review, only one studyx30Combes, X., Andriamifidy, L., Dufresne, E. et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth. 2007; 99: 276–281

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from our review was included. Furthermore, there was no bias assessment, and the review did not include any meta-analyses. This review reported postoperative sore throat with a prevalence of up to 62%. In a Cochrane review on lidocaine for preventing postoperative sore throat,x68Tanaka, Y., Nakayama, T., Nishimori, M., Tsujimura, Y., Kawaguchi, M., and Sato, Y. Lidocaine for preventing postoperative sore throat. Cochrane Database Syst Rev. 2015; 7: Cd004081

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the crude prevalence of sore throat was 20–30% pending the use of lidocaine. In our assessment, the crude prevalence was 33%.

Limitations and quality of evidence

About half of the included trials were using a (modified) intubation score according to “Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents” (GRPC-score) by Viby-Mogensen and colleagues.x60Viby-Mogensen, J., Engbaek, J., Eriksson, L.I. et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand. 1996; 40: 59–74

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, x66Fuchs-Buder, T., Claudius, C., Skovgaard, L.T., Eriksson, L.I., Mirakhur, R.K., and Viby-Mogensen, J. bag Cross Mini Pink 'Holly Bag Body' Carvela Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision.Acta Anaesthesiol Scand. 2007; 51: 789–808

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Further, a major part of the remaining trials used intubation scores where many of the elements from the GRPC-score were used. Thus, to some extent there was agreement across the included trials on how to define DTI. Even though the trials used a defined outcome in accordance with what is recommended in research concerning NMBA, it differs from the definitions traditionally used in research on difficult airway management.x4Lundstrom, L.H., Moller, A.M., Rosenstock, C., Astrup, G., Gatke, M.R., and Wetterslev, J. Avoidance of neuromuscular blocking agents may increase the risk of difficult tracheal intubation: a cohort study of 103,812 consecutive adult patients recorded in the Danish Anaesthesia Database. Br J Anaesth. 2009; 103: 283–290

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, x69Adnet, F., Borron, S.W., Racine, S.X. et al. The intubation difficulty scale (IDS): proposal and evaluation of a new score characterizing the complexity of endotracheal intubation. Anesthesiology. 1997; 87: 1290–1297

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Although, there is a lack of consensus in the literature, these definitions often describe multiple (unsuccessful) attempts at intubation, shift to more advanced intubation techniques, or other personnel performing the airway management.x64Norskov, A.K., Wetterslev, J., Rosenstock, C.V. et al. Effects of using the simplified airway risk index vs usual airway assessment on unanticipated difficult tracheal intubation—a cluster randomized trial with 64,273 participants. Br J Anaesth. 2016; 116: 680–689

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, x69Adnet, F., Borron, S.W., Racine, S.X. et al. The intubation difficulty scale (IDS): proposal and evaluation of a new score characterizing the complexity of endotracheal intubation. Anesthesiology. 1997; 87: 1290–1297

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, x70Practice guidelines for management of the difficult airway. A report by the American society of Anesthesiologists task force on management of the difficult airway. Anesthesiology. 1993; 78: 597–602

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One must therefore bear in mind that our primary outcome may not reflect a situation that most clinicians consider a real difficult intubation, threatening the patient's life or health. Thus, there is a substantial degree of indirectness concerning our primary outcome describing DTI. Regarding upper airway discomfort and injury, the outcome measures varied in the various trials. Likewise, by whom, how, and when the outcome measure was evaluated differed or was not clearly stated in some of these trials. The potential heterogeneity of the outcome definitions across the included trials, especially concerning upper airway injury and discomfort must be considered when interpreting our results in a clinical context.

We present our main results on all the investigated outcomes in the summary of findings tables (Table 1Table 1) grading the quality of the evidence according to GRADE,x24Guyatt, G.H., Oxman, A.D., Kunz, R. et al. GRADE guidelines 6. Rating the quality of evidence—imprecision. J Clin Epidemiol. 2011; 64: 1283–1293

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, x25Guyatt, G.H., Oxman, A.D., Santesso, N. et al. GRADE guidelines: 12. Preparing summary of findings tables—binary outcomes. J Clin Epidemiol. 2013; 66: 158–172

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stressing the meta-analyses results originating from trials with overall low risk of bias. Between-trial heterogeneity varied from absent to substantial in the various meta-analyses concerning our different outcomes. This may emphasise the bias risk and the diversity of the dose finding regimens in the different trials, using substantially different combinations of adjuvant drugs and NMBA. Further, the minor differences in definitions of a DTI may in some degree contribute to the heterogeneity. In contrast, there was no between-trial heterogeneity regarding direct laryngoscopy which may be explained by a well-defined outcome measurex10Cormack, R.S. and Lehane, J. Difficult tracheal intubation in obstetrics. Anaesthesia. 1984; 39: 1105–1111

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retrievable from all 13 trials.

We calculated TSA-adjusted CIs considering sparse data and multiple testing because of potentially repeated updates of the cumulative meta-analyses to control the risk of random errors and to prevent premature statements of superiority of one intervention compared with another.x15Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009; 9: 86

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, x22Wetterslev, J., Thorlund, K., Brok, J., and Gluud, C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008; 61: 64–75

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, x23Brok, J., Thorlund, K., Gluud, C., and Wetterslev, J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008; 61: 763–769

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, x72Thorlund, K., Imberger, G., Walsh, M. et al. The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis—a simulation study. PLoS One. 2011; 6: e25491

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TSA revealed that all our meta-analyses of the primary outcomes have a very low degree of impression, hereby indicating a low risk of random error.

Pink 'Holly Body' bag Bag Carvela Mini Cross In the individual RCTs of this review, it is often emphasised that the incidence of disadvantages of NMBA may be a major reason for avoiding NMBA in airway management. It was a noticeable limitation that the evaluation of the effect of avoidance of NMBA compared with the use of NMBA on the occurrence of (S)AE is virtually absent. None of the trials evaluated the effect on mortality (short- or long-term) and only one trial the effect on other types of (S)AE reporting one (S)AE. After completing this review, we do not know whether the lack of reported side effects is as a result of ‘silence’ because (S)AEs were not observed/registered or actually ‘absent’.

In most of the included trials the cut off values defining a DTI were clearly stated. However, in five trials,x28Beck, G.N., Masterson, G.R., Richards, J., and Bunting, P. Comparison of intubation following propofol and alfentanil with intubation following thiopentone and suxamethonium. Anaesthesia. 1993; 48: 876–880

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, x33Gulhas, N., Topal, S., Erdogan Kayhan, G. et al. Remifentanil without muscle relaxants for intubation in microlaryngoscopy: a double blind randomised clinical trial. Eur Rev Med Pharmacol Sci. 2013; 17: 1967–1973

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, x44McNeil, I.A., Culbert, B., and Russell, I. Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 micrograms kg-1 or 4 micrograms kg-1. Br J Anaesth. 2000; 85: 623–625

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, x53Scheller, M.S., Zornow, M.H., and Saidman, L.J. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg. 1992; 75: 788–793

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, x56Stevens, J.B., Vescovo, M.V., Harris, K.C., Walker, S.C., and Hickey, R. Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?. Anesth Analg. 1997; 84: 1222–1226

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different composite scores were used without defined cut-offs. In assessing these trials, we used the underlying references or comparable scores to define a cut off value enabling us to include the trials in our meta-analyses. Thus, some degree of interpretation of the outcome measures was necessary and, as a consequence, our assessments may have introduced bias. Nevertheless, we believe that this categorisation was justifiable considering the existing literature and we therefore consider the risk of introducing bias as low.

In six trials,x35Harsten, A. and Gillberg, L. Intubating conditions provided by propofol and alfentanil—acceptable, but not ideal. Acta Anaesthesiol Scand. 1997; 41: 985–987

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, x38Jiao, J., Huang, S., Chen, Y., Liu, H., and Xie, Y. Comparison of intubation conditions and apnea time after anesthesia induction with propofol/remifentanil combined with or without small dose of succinylcholine. Int J Clin Exp Med. 2014; 7: 393–399

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, x45Mencke, T., Echternach, M., Kleinschmidt, S. et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial. Anesthesiology. 2003; 98: 1049–1056

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, x46Mencke, T., Jacobs, R.M., Machmueller, S. et al. Intubating conditions and side effects of propofol, remifentanil and sevoflurane compared with propofol, remifentanil and rocuronium: a randomised, prospective, clinical trial. BMC Anesthesiol. 2014; 14: 39

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, x49Nimmo, S.M., McCann, N., Broome, I.J., and Robb, H.M. Effectiveness and sequelae of very low-dose suxamethonium for nasal intubation. Br J Anaesth. 1995; 74: 31–34

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, x55Sivalingam, P., Kandasamy, R., Dhakshinamoorthi, P., and Madhavan, G. Tracheal intubation without muscle relaxant—a technique using sevoflurane vital capacity induction and alfentanil. Anaesth Intensive Care. 2001; 29: 383–387

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the authors excluded a few patients from their assessments if tracheal intubation failed. We consider these patients as truly difficult to intubate and therefore we chose to include them in our meta-analyses. This may have introduced bias; however, a sensitivity analysis excluding these patients from our meta-analyses did not change the conclusion.

Conclusion

This review supports that the use of NMBA may create better conditions for tracheal intubation in clinical practice than avoidance of NMBA. In trials with an overall low risk of bias, there was a significantly increased risk of DTI with no use of NMBA with a RR of 13.3 and for all included trials this association was confirmed with a RR of 5.0. The results were characterised by indirectness concerning our primary outcome describing DTI. Based on the defined outcomes in the included trials, our primary outcome may not reflect a situation that most clinicians consider to be a clinically important DTI where the patient's life or health may be threatened. Thus, we could not conclude with certainty that the avoidance of NMBA was associated with a clinically important or serious difficult intubation. A difficult laryngoscopy, as defined by Cormack and Lehane, may be a reasonable surrogate for a clinically serious difficult airway. Our results indicate that avoiding NMBA increases the risk of a difficult laryngoscopy, but after TSA adjustment of the CI, firm evidence could not be established.

Concerning our other primary outcome, ‘events of upper airway discomfort or injury’, there were only few data from trials with low risk of bias. Among all trials, there was a firm and significant risk of upper airway discomfort or injury when avoiding NMBA. Of specific notice is the fact that the evaluation of the effect of avoidance of NMBA compared with the use of NMBA on the occurrence of SAE is virtually absent as none of the trials evaluated the effect on mortality (short- or long-term). There is implication for future research focusing on the impact of avoiding NMBA on the prevalence of severe intubation difficulties and difficult laryngoscopy as categorised by Cormack and Lehane. In addition, large trials with low risk of bias describing upper airway injury and discomfort, and other SAEs and mortality are needed.

In conclusion, in a clinical context one must balance arguments for using or not using NMBA when performing tracheal intubation.

Authors' contributions

Designing the review: L.H.L., J.W., A.M.M., S.S.

Screening search results: L.H.L., C.D., A.N.

Screening retrieved papers against inclusion criteria and abstracting data from papers: L.H.L., C.D., A.N., C.V.R., J.T.

Data management for the review: L.H.L., C.D., A.N.

Statistical analysis: L.H.L., J.W.

Interpretation of data: L.H.L., A.M.M., J.W.

Writing the review: all authors.

Acknowledgements

We would like to thank Karen Hovhannisyan and Janne Vendt (former and present Cochrane Anaesthesia, Critical and Emergency Care Group Information specialist, respectively) for their valuable help with the phrasing of the search strategies. We would like to thank Andrew Smith (content editor), Marialena Trivella (statistical editor), Rodrigo Cavallazzi, Shahla Siddiqui, Fred Cheney (peer reviewers), and Tracey Lloyd (representative of ACE's consumer panel) for their help and editorial advice during the preparation of the protocol.x9Lundstrøm, L.H., Strande, S., Møller, A.M., and Wetterslev, J. Use versus avoidance of neuromuscular blocking agent for improving conditions during tracheal intubation or direct laryngoscopy in adults and adolescents (Protocol). Cochrane Database Syst Rev. 2011; 7: CD009237

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We would like to thank Andrew Smith (content editor), Jing Xie (statistical editor), Emmanuel Boselli, Thomas Mencke (peer reviewers), Brian Stafford (consumer referee) for their help and editorial advice during the preparation of this systematic review. We would like to thank Julie Wetterslev for helping with Spanish translation.

Appendix A. Supplementary data

Declaration of interest

L.H.L., A.M.M., C.R., J.W. were co-authors of an observational study entitled ‘Avoidance of neuromuscular blocking agents may increase the risk of difficult tracheal intubation: a cohort study of 103,812 consecutive adult patients recorded in the Danish Anaesthesia Database’.4 J.W. is a member of the task force in the Copenhagen Trial Unit, developing theory, software, and manuals for TSA. A.M.M. is a Co-ordinating Editor of The Cochrane Anaesthesia, Critical and Emergency Care Group and editorial board member of British Journal of Anaesthesia. J.T. received grants for two studies through Merck Investigator Studies Program in 2016 and 2017. Aim of the two studies: (1) to assess the use of neuromuscular monitoring and the incidence of residual neuromuscular blockade in six Danish anaesthesia departments; (2) to assess the effect of an e-learning course in neuromuscular monitoring.

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This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews 2017, Issue 5, DOI: 10.1002/14651858. CD009237.pub2 (see www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback, and the database should be consulted for the most recent version of the review.

This article is accompanied by an editorial: Optimising conditions for tracheal intubation: should neuromuscular blocking agents always be used? by J.M. Hunter, Br J Anesth 2018:120:1150–1153, doi: 10.1016/j.bja.2018.01.043

© 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
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