Lars H Lundstrøm, Christophe Hv Duez, Anders K Nørskov, Charlotte V Rosenstock, Jakob L Thomsen, Ann Merete Møller, Søren Strande, Jørn Wetterslev

Tracheal intubation during induction of general anaesthesia is a vital procedure performed to secure a patient's airway. Several studies have identified difficult tracheal intubation (DTI) or failed tracheal intubation as one of the major contributors to anaesthesia-related mortality and morbidity. Use of neuromuscular blocking agents (NMBA) to facilitate tracheal intubation is a widely accepted practice. However, because of adverse effects, NMBA may be undesirable. Cohort studies have indicated that avoiding NMBA is an independent risk factor for difficult and failed tracheal intubation. However, no systematic review of randomized trials has evaluated conditions for tracheal intubation, possible adverse effects, and postoperative discomfort. To evaluate the effects of avoiding neuromuscular blocking agents (NMBA) versus using NMBA on difficult tracheal intubation (DTI) for adults and adolescents allocated to tracheal intubation with direct laryngoscopy. To look at various outcomes, conduct subgroup and sensitivity analyses, examine the role of bias, and apply trial sequential analysis (TSA) to examine the level of available evidence for this intervention. We searched CENTRAL, MEDLINE, Embase, BIOSIS, International Web of Science, LILACS, advanced Google, CINAHL, and the following trial registries: Current Controlled Trials; ClinicalTrials.gov; and www.centerwatch.com, up to January 2017. We checked the reference lists of included trials and reviews to look for unidentified trials. We included randomized controlled trials (RCTs) that compared the effects of avoiding versus using NMBA in participants 14 years of age or older. Two review authors extracted data independently. We conducted random-effects and fixed-effect meta-analyses and calculated risk ratios (RRs) and their 95% confidence intervals (CIs). We used published data and data obtained by contacting trial authors. To minimize the risk of systematic error, we assessed the risk of bias of included trials. To reduce the risk of random errors caused by sparse data and repetitive updating of cumulative meta-analyses, we applied TSA. We identified 34 RCTs with 3565 participants that met our inclusion criteria. All trials reported on conditions for tracheal intubation; seven trials with 846 participants described 'events of upper airway discomfort or injury', and 13 trials with 1308 participants reported on direct laryngoscopy. All trials used a parallel design. We identified 18 dose-finding studies that included more interventions or control groups or both. All trials except three included only American Society of Anesthesiologists (ASA) class I and II participants, 25 trials excluded participants with anticipated DTI, and obesity or overweight was an excluding factor in 13 studies. Eighteen trials used suxamethonium, and 18 trials used non-depolarizing NMBA.Trials with an overall low risk of bias reported significantly increased risk of DTI with no use of NMBA (random-effects model) (RR 13.27, 95% CI 8.19 to 21.49; P < 0.00001; 508 participants; four trials; number needed to treat for an additional harmful outcome (NNTH) = 1.9, I(2) = 0%, D(2) = 0%, GRADE = moderate). The TSA-adjusted CI for the RR was 1.85 to 95.04. Inclusion of all trials resulted in confirmation of results and of significantly increased risk of DTI when an NMBA was avoided (random-effects model) (RR 5.00, 95% CI 3.49 to 7.15; P < 0.00001; 3565 participants; 34 trials; NNTH = 6.3, I(2) = 70%, D(2) = 82%, GRADE = low). Again the cumulative z-curve crossed the TSA monitoring boundary, demonstrating harmful effects of avoiding NMBA on the proportion of DTI with minimal risk of random error. We categorized only one trial reporting on upper airway discomfort or injury as having overall low risk of bias. Inclusion of all trials revealed significant risk of upper airway discomfort or injury when an NMBA was avoided (random-effects model) (RR 1.37, 95% CI 1.09 to 1.74; P = 0.008; 846 participants; seven trials; NNTH = 9.1, I(2) = 13%, GRADE = moderate). The TSA-adjusted CI for the RR was 1.00 to 1.85. None of these trials reported mortality. In terms of our secondary outcome 'difficult laryngoscopy', we categorized only one trial as having overall low risk of bias. All trials avoiding NMBA were significantly associated with difficult laryngoscopy (random-effects model) (RR 2.54, 95% CI 1.53 to 4.21; P = 0.0003; 1308 participants; 13 trials; NNTH = 25.6, I(2) = 0%, D(2)= 0%, GRADE = low); however, TSA showed that only 6% of the information size required to detect or reject a 20% relative risk reduction (RRR) was accrued, and the trial sequential monitoring boundary was not crossed. This review supports that use of an NMBA may create the best conditions for tracheal intubation and may reduce the risk of upper airway discomfort or injury following tracheal intubation. Study results were characterized by indirectness, heterogeneity, and high or uncertain risk of bias concerning our primary outcome describing difficult tracheal intubation. Therefore, we categorized the GRADE classification of quality of evidence as moderate to low. In light of defined outcomes of individual included trials, our primary outcomes may not reflect a situation that many clinicians consider to be an actual difficult tracheal intubation by which the patient's life or health may be threatened.