The final multivariate logistic regression model for AREs is shown in Table 5. Although AREs were associated with RNMB in the univariate analysis (unadjusted RR, 1.52 [95% CI, 1.05–2.12]), after adjusting for core temperature and level of consciousness, the association between AREs and RNMB was statistically insignificant in the multivariate analysis (adjusted RR, 1.46 [95% CI, 0.99–2.08]). The associations between AREs and temperature (adjusted RR, 1.43 [95% CI, 1.04–1.92] per 1°C decrease) and AREs and level of consciousness (adjusted RR, 4.76 [95% CI, 1.49–6.76] for unrousable/unconscious compared with alert/awake) remained to be statistically significant, after adjustments. This suggests that hypothermia and reduced level of consciousness were significant intervening factors in the relationship between RNMB and AREs.
The prevalence of RNMB in our cohort was 31% (27%–35%), which was consistent with the previous research.9 It is concerning that the prevalence of RNMB remains high, despite the growing body of evidence about its adverse effects.1–6 This study identified older age, open abdominal surgery, and shorter duration of operation (<90 minutes) as independent risk factors for RNMB on admission to the PACU (Table 3).
Altered pharmacokinetics and pharmacodynamics in the elderly prolong the duration of action of muscle relaxants. Therefore, the increased depth of blockade may not be adequately reversed with neostigmine at the end of surgery. This prolonged duration of action of the intermediate action ND-NMBA in the elderly patient may not be widely appreciated.
The association between RNMB and open abdominal surgery may be expected. Surgeons may require deeper blockade for closure of the abdominal cavity, and anesthesiologists may delay reversal until closure is complete. A number of research articles and meta-analyses have reported that surgical conditions for some open and laparoscopic procedures may be improved by the use of deep neuromuscular blockade, and the more sensitive pharyngeal and upper airway muscles cannot be easily or rapidly reversed by neostigmine.21–24 However, this is controversial; recently, Kopman and Naguib25 have reviewed the literature on the value of deep blockade in laparoscopic surgery and concluded that there is little or no evidence to suggest that using deep neuromuscular blockade (as opposed to a blockade of moderate degree) for laparoscopic surgery will improve surgical operating conditions.
Similarly, shorter operation duration may not allow sufficient time for the spontaneous recovery of neuromuscular blockade to a TOF ratio of 0.90 or above, or a level that is shallow enough for neostigmine to provide effective reversal. It is well recognized that neostigmine exhibits a ceiling effect where administration of greater than 50 to 70 μg/kg will produce no increase in the inhibition of acetylcholinesterase, although further research is required to determine the precise maximal effective dose. No patients were administered additional neostigmine in the PACU.
Neostigmine administration was associated with a 50% increase in RNMB in univariate analysis. Although reversal with neostigmine was attempted in 403 (82.4%) of patients, the incidence of RNMB was greater in subjects who received this agent (33.1%), compared with those who did not receive any (22.8%; P = .04; Table 2).
Because neuromuscular function monitoring was used infrequently, neostigmine may have been administered when the neuromuscular block was too deep or inadequate time was allowed for the reversal to occur. With maximal inhibition of acetylcholinesterase, no further increase in acetylcholine can be achieved at the neuromuscular junction. Second, neostigmine may induce a paradoxical muscle weakness if used in subjects who have already achieved complete recovery from NMB. Upper airway collapsibility and an impairment of genioglossus and diaphragm function have been documented in rats and healthy human volunteers. Although not completely understood, proposed mechanisms include desensitization of the acetylcholine receptors, depolarizing blockade, and open channel blockade. The 41% increase in the RR of RNMB when neostigmine is used became insignificant in the multivariate analysis. Increasing age, open abdominal surgery, and the duration of surgery <90 minutes were significant associations with RNMB in this analysis.
Anesthesiologists may be more likely to administer neostigmine for the attempted reversal of ND-NMBA in patients undergoing shorter operations or open abdominal surgery. These patients are at higher risk of RNMB and are more likely to have deeper neuromuscular blockade. However, neostigmine can only effectively reverse shallow blockade demonstrated by ≥2 twitches on TOF ratio monitoring, and it is known to have a variable onset of action.26,27 Therefore, quantitative neuromuscular function monitoring has been recommended to aid the selection, timing, and dose of the most appropriate reversal agent and to assess the effectiveness of reversal before extubation.27,28
In our study, RNMB was not associated with the type of ND-NMBA used or neuromuscular function monitoring. Only 24% of the patients had some form of neuromuscular function monitoring, but it was not possible to distinguish whether this was subjective or objective or how this was used by the anesthesiologist. Objective monitoring may have been used only to assess adequate depth of blockade during surgery and not to assess the timing, dose, or effectiveness of reversal. Subjective monitors cannot exclude RNMB. Approximately 80% of patients received neostigmine at the end of the operation. Therefore, it is evident that the majority of patients who received neostigmine did not have any form of neuromuscular function monitoring, and the anesthesiologist could not have assessed the depth of blockade at the time of neostigmine administration. Furthermore, the majority of patients could not have had the efficacy of reversal assessed quantitatively at the time of extubation.
The prevalence of RNMB detected using EMG in this study was consistent with the previous studies that used acceleromyography (AMG).29–31 Some AMG devices may produce baseline readings of up to 1.47 before administration of ND-NMBA and require normalization of the TOF ratio.32 However, this was not performed in all studies and limits the accuracy of their results. Liang et al found that AMG overestimates the TOF ratio by approximately 0.15 and is significantly less precise than EMG. Kopman found that AMG overestimates the TOF ratio by only 6% to 8% at high levels of recovery (AMG TOF ratio of 0.90), but this difference increases to 10% to 12% at AMG TOF ratio of 0.70.15,33 Furthermore, AMG may be inaccurate in recovering patients in the PACU as voluntary or reflex resistance to the electrical stimulus may alter the mechanical response recorded by AMG.34 EMG is considered by many as a clinical gold standard for detecting RNMB because it has high precision and is equivalent to mechanomyography during the late phase of recovery.12–18 We recorded TOF ratios using EMG at the abductor digiti minimi muscle. Compared with other muscle groups in the hand, this is the most precise location for EMG recording and the least affected by small variations in electrode position.10,16
AREs were identified using criteria for “critical respiratory events” defined by Murphy et al3,19 with slight modification to accommodate local PACU practice: the criterion based on the administration of oxygen at 3 l/min through nasal speculum was changed to 6 l/min through facemask (Table 1). The prevalence of AREs was much higher in our cohort (16%) compared with Murphy’s original study (0.8%). However, our finding is consistent with a number of more recent studies that have reported the prevalence of AREs to be between 10% and 40%.29–31,35–37
Differences in observed prevalence of AREs are most likely due to the predominant use of deep extubation at our institution. Ninety-three percent of patients who entered our PACU had their level of consciousness classified as being other than “alert and awake.” Although our PACU nursing staff are trained and experienced in the management of patients with decreased level of consciousness, deep extubation has raised safety concerns, and this may not be the usual practice in many institutions. Transfer of the patients to PACU in an “awake and alert” state may provide additional safety and reduce the risk of AREs. Deep extubation reduces the incidence of coughing, bucking, and the hemodynamic effects of tracheal tube movement, but these advantages are offset by an increased incidence of upper airway obstruction.38–42 The original Murphy study did not report the level of consciousness or patient positioning.
The 8 Murphy criteria for “critical respiratory events” are not equal in severity (Table 1). Upper airway obstruction was the most common ARE observed in our cohort, and it may be corrected by maneuvers such as jaw thrust, insertion of an oral airway, or lateral positioning. Jaw thrust may be considered as routine management in the PACU and not critical. However, its early recognition and management are critical to prevent further deterioration to severe hypoxemia and its associated complications. A higher prevalence of upper airway obstruction that was recognized early and corrected appropriately in our cohort may explain the lower prevalence of hypoxemia we observed compared with others.21–23
We identified lower core temperature and reduced level of consciousness as independent risk factors for AREs (Table 5). Although the association between AREs and RNMB was not statistically significant in our multivariate analysis, its P value is close to .05, and previous studies have found statistically significant links, although these studies did not adjust for level of consciousness.30,31,35,36 Hypothermia and reduced level of consciousness are significant intervening factors in this association with the latter being of greatest impact (2–3 times greater than either RNMB or hypothermia). In particular, we found that a small (0.2°C) difference in median core temperature was statistically significant (Table 4). Although such a small temperature change is unlikely to cause clinically significant effect, logistic regression modeling showed that this corresponded to a 43% increase in risk of ARE per 1°C drop in core temperature and hence is clinically important.
RNMB may, depending on the severity of blockade, cause upper airway obstruction, decreased pulmonary function, impaired pharyngeal reflexes and muscle coordination, increased risk of aspiration, and impaired hypoxic ventilatory response.1–6 In addition, RNMB may contribute to hypothermia by inhibiting the shivering response and cause reduced level of consciousness by inhibiting arousal and motor responses.
The association between AREs and decreased core temperature may not be widely recognized. Mild hypothermia reduces the minimum alveolar concentration for inhalational agents and reduces the metabolism of other anesthetic agents.43,44 This may contribute to decreased level of consciousness and increased risk of upper airway obstruction.
The association between AREs and reduced level of consciousness is well recognized and understood. However, previous studies examining the relationship between RNMB and AREs often omit to report or adjust for level of consciousness. In our analysis, decreased level of consciousness was significantly associated with increased risk of AREs. Inclusion of level of consciousness as a covariate weakened the association between RNMB and AREs (unadjusted RR, 1.52 [95% CI, 1.05–2.12]; adjusted RR, 1.46 [95% CI, 0.99–2.08]), suggesting that it is a significant intervening factor.
This study has a number of limitations. First, a prospective observational study cannot establish causality. The risk factors for AREs identified in this study may be reversible causes and warrant further investigation by high-quality randomized controlled trials. Second, the EMG stimulus was limited to 30 mA as it minimizes pain in awake or lightly sedated patients.34 However, the stimulus may be submaximal and result in reduced accuracy of measurement.45 Third, the prevalence of AREs may be underestimated in our study because we were unable to include patients having operations after 8 am to 8 pm and patients who were transferred directly to the intensive care unit. These were often emergency or high-risk patients, who may be at an increased risk of AREs. Furthermore, the observed prevalence of ARE is affected by variations in study protocols and local practices (eg, criteria for extubation, patient recovery position, oxygen delivery method). Hence, our results may not be generalizable or comparable with other studies. Fourth, we did not have ethics approval or sufficient research personnel to follow-up patients after discharge from the PACU. The long-term morbidity and mortality outcomes of patients with RNMB and AREs in the PACU warrant further investigation. Finally, our statistical analysis was not adjusted for multiple testing, and associations other than that between RNMB and ARE were part of exploratory analysis, rather than confirmatory analysis of previously found associations. Therefore, it is plausible that we detected some associations by chance alone and particularly those with P values near .05 should be interpreted with caution. This is most relevant regarding the association of age and neostigmine with RNMB and core temperature with ARE because they were also not a priori specified for statistical testing in our protocol. Further studies are required to confirm these associations.
The prevalence of RNMB in our PACU is >30%. Although a significantly greater proportion of AREs had RNMB, it was not found to be an independent predictor of AREs. Hypothermia and reduced level of consciousness were the only independent risk factors for AREs in our study, and these findings need to be confirmed by future studies. Older patients, those undergoing open abdominal surgery, or having shorter operations may be at a higher risk of RNMB. At institutions with limited availability of quantitative neuromuscular function monitors, our findings suggest that these groups should receive priority for their use. Further investigations are warranted to examine the benefits of careful selection of reversal agent, its dosage, and timing in these high-risk groups. Administration of neostigmine without objective neuromuscular function monitoring may not guarantee adequate reversal of neuromuscular blockade. Transfer of the patients to PACU in an “awake and alert” state may provide additional safety and reduce the risk of AREs.
Name: Paul A. Stewart, MBBS, FANZCA.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Conflicts of Interest: Paul A. Stewart received MSD unrestricted research grant, lecture honoraria; GE Healthcare Equipment loan and lecture honoraria; and Jackson Rees Research Grant, Australian Society of Anaesthetists.
Name: Sophie S. Liang, BSc (Adv), GStat, MBBS (Hons), MMed (Clin Epi).
Contribution: This author helped design the study, plan, supervise and conduct the statistical analysis, and write the manuscript.
Conflicts of Interest: Sophie S. Liang declares no conflicts of interest.
Name: Qiushuang Susan Li, MBBS.
Contribution: This author helped collect data, conduct the interim statistical analysis, and write the manuscript.
Conflicts of Interest: Qiushuang Susan Li declares no conflicts of interest.
Name: Min Li Huang, BMedSci (Hons), MBBS.
Contribution: This author helped collect data and conduct the interim statistical analysis.
Conflicts of Interest: Min Li Huang declares no conflicts of interest.
Name: Ayse B. Bilgin, BEng, MBA, MMaths, PhD, PostGradDipHE
Contribution: This author helped plan, supervise and conduct the statistical analysis, and write the manuscript.
Conflicts of Interest: Ayse B. Bilgin declares no conflicts of interest.
Name: Dukyeon Kim, BSc (Adv).
Contribution: This author helped conduct the statistical analysis and write the manuscript.
Conflicts of Interest: Dukyeon Kim declares no conflicts of interest.
Name: Stephanie Phillips, BMed, FANZCA, FRCA.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Conflicts of Interest: Stephanie Phillips received MSD unrestricted research grant and Jackson Rees Research Grant, Australian Society of Anaesthetists.
This manuscript was handled by: Ken B. Johnson, MD.
1. Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology. 1993;78:693699.
2. Eriksson LI, Sundman E, Olsson R, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology. 1997;87:10351043.
3. Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg. 2008;107:130137.
4. Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010;111:120128.
5. Pedersen T. Complications and death following anaesthesia. A prospective study with special reference to the influence of patient-, anaesthesia-, and surgery-related risk factors. Dan Med Bull. 1994;41:319331.
6. Shorten GD. Postoperative residual curarisation: incidence, aetiology and associated morbidity. Anaesth Intensive Care. 1993;21:782789.
7. Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. Part II: methods to reduce the risk of residual weakness. Anesth Analg. 2010;111:129140.
8. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg. 2010;111:110119.
9. Phillips S, Bilgin A, Stewart P. A survey of practice and attitudes of Australasian anaesthetists to neuromuscular transmission monitoring in 2011. Anaesth Intensive Care. 2012;40:1065.
10. Smans J, Korsten HH, Blom JA. Optimal surface electrode positioning for reliable train of four muscle relaxation monitoring. Int J Clin Monit Comput. 1996;13:920.
11. Fuchs-Buder T, Claudius C, Skovgaard LT, Eriksson LI, Mirakhur RK, Viby-Mogensen J; 8th International Neuromuscular Meeting. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand. 2007;51:789808.
12. Engbaek J, Roed J, Hangaard N, Viby-Mogensen J. The agreement between adductor pollicis mechanomyogram and first dorsal interosseous electromyogram. A pharmacodynamic study of rocuronium and vecuronium. Acta Anaesthesiol Scand. 1994;38:869878.
13. Kopman AF. The relationship of evoked electromyographic and mechanical responses following atracurium in humans. Anesthesiology. 1985;63:208211.
14. Kopman AF, Chin W, Cyriac J. Acceleromyography vs. electromyography: an ipsilateral comparison of the indirectly evoked neuromuscular response to train-of-four stimulation. Acta Anaesthesiol Scand. 2005;49:316322.
15. Liang SS, Stewart PA, Phillips S. An ipsilateral comparison of acceleromyography and electromyography during recovery from nondepolarizing neuromuscular block under general anesthesia in humans. Anesth Analg. 2013;117:373379.
16. Phillips S, Stewart PA, Freelander N, Heller G. Comparison of evoked electromyography in three muscles of the hand during recovery from non-depolarising neuromuscular blockade. Anaesth Intensive Care. 2012;40:690696.
17. Shanks CA, Jarvis JE. Electromyographic and mechanical twitch responses following suxamethonium administration. Anaesth Intensive Care. 1980;8:341344.
18. Stewart PA, Freelander N, Liang S, Heller G, Phillips S. Comparison of electromyography and kinemyography during recovery from non-depolarising neuromuscular blockade. Anaesth Intensive Care. 2014;42:378384.
19. Murphy GS, Szokol JW, Marymont JH, et al. Intraoperative acceleromyographic monitoring reduces the risk of residual neuromuscular blockade and adverse respiratory events in the postanesthesia care unit. Anesthesiology. 2008;109:389398.
20. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280:16901691.
21. Williams MT, Rice I, Ewen SP, Elliott SM. A comparison of the effect of two anaesthetic techniques on surgical conditions during gynaecological laparoscopy. Anaesthesia. 2003;58:574578.
22. Martini CH, Boon M, Bevers RF, Aarts LP, Dahan A. Evaluation of surgical conditions during laparoscopic surgery in patients with moderate vs deep neuromuscular block. Br J Anaesth. 2014;112:498505.
23. Staehr-Rye AK, Rasmussen LS, Rosenberg J, et al. Surgical space conditions during low-pressure laparoscopic cholecystectomy with deep versus moderate neuromuscular blockade: a randomized clinical study. Anesth Analg. 2014;119:10841092.
24. Madsen MV, Staehr-Rye AK, Gätke MR, Claudius C. Neuromuscular blockade for optimising surgical conditions during abdominal and gynaecological surgery: a systematic review. Acta Anaesthesiol Scand. 2015;59:116.
25. Kopman AF, Naguib M. Laparoscopic surgery and muscle relaxants: is deep block helpful? Anesth Analg. 2015;120:5158.
26. Sasaki N, Meyer MJ, Malviya SA, et al. Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study. Anesthesiology. 2014;121:959968.
27. Kopman AF, Eikermann M. Antagonism of non-depolarising neuromuscular block: current practice. Anaesthesia. 2009;64(Suppl 1):2230.
28. Kopman AF, Zank LM, Ng J, Neuman GG. Antagonism of cisatracurium and rocuronium block at a tactile train-of-four count of 2: should quantitative assessment of neuromuscular function be mandatory? Anesth Analg. 2004;98:102106.
29. Esteves S, Martins M, Barros F, et al. Incidence of postoperative residual neuromuscular blockade in the postanaesthesia care unit: an observational multicentre study in Portugal. Eur J Anaesthesiol. 2013;30:243249.
30. Norton M, Xará D, Parente D, Barbosa M, Abelha FJ. Residual neuromuscular block as a risk factor for critical respiratory events in the post anesthesia care unit. Rev Esp Anestesiol Reanim. 2013;60:190196.
31. Yip PC, Hannam JA, Cameron AJ, Campbell D. Incidence of residual neuromuscular blockade in a post-anaesthetic care unit. Anaesth Intensive Care. 2010;38:9195.
32. Suzuki T, Fukano N, Kitajima O, Saeki S, Ogawa S. Normalization of acceleromyographic train-of-four ratio by baseline value for detecting residual neuromuscular block. Br J Anaesth. 2006;96:4447.
33. Kopman AF, Chin W, Cyriac J. Acceleromyography vs. electromyography: an ipsilateral comparison of the indirectly evoked neuromuscular response to train-of-four stimulation. Acta Anaesthesiol Scand. 2005;49:316322.
34. Baillard C, Bourdiau S, Le Toumelin P, et al. Assessing residual neuromuscular blockade using acceleromyography can be deceptive in postoperative awake patients. Anesth Analg. 2004;2004:854857.
35. Sauer M, Stahn A, Soltesz S, Noeldge-Schomburg G, Mencke T. The influence of residual neuromuscular block on the incidence of critical respiratory events. A randomised, prospective, placebo-controlled trial. Eur J Anaesthesiol. 2011;28:842848.
36. Cammu GV, Smet V, De Jongh K, Vandeput D. A prospective, observational study comparing postoperative residual curarisation and early adverse respiratory events in patients reversed with neostigmine or sugammadex or after apparent spontaneous recovery. Anaesth Intensive Care. 2012;40:9991006.
37. Pietraszewski P, Gaszyński T. Residual neuromuscular block in elderly patients after surgical procedures under general anaesthesia with rocuronium. Anaesthesiol Intensive Ther. 2013;45:7781.
38. Popat M, Mitchell V, Dravid R, Patel A, Swampillai C, Higgs A. Difficult airway society guidelines for the management of tracheal extubation. Anaesthesia. 2012;67:318340.
39. Practice guidelines for management of the difficult airway: an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology. 2003;98:12691277.
40. Petrini F, Accorsi A, Adrario E, et al.; Gruppo di Studio SIAARTI “Vie Aeree Difficili”; IRC e SARNePI; Task Force. Recommendations for airway control and difficult airway management. Minerva Anestesiol. 2005;71:617657.
41. Boisson-Bertrand D, Bourgain JL, Camboulives J, et al. [Difficult intubation. French Society of Anesthesia and Intensive Care. A collective expertise]. Ann Fr Anesth Reanim. 1996;15:207214.
42. Crosby ET, Cooper RM, Douglas MJ, et al. The unanticipated difficult airway with recommendations for management. Can J Anaesth. 1998;45:757776.
43. Sessler DI. Miller RD. Temperature monitoring. 2005:6th ed. Philadelphia: Elsevier, Churchill Livingstone, 15711597.
44. Leslie K, Sessler DI, Bjorksten AR, Moayeri A. Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesth Analg. 1995;80:10071014.
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45. Helbo-Hansen HS, Bang U, Nielsen HK, Skovgaard LT. The accuracy of train-of-four monitoring at varying stimulating currents. Anesthesiology. 1992;76:199203.