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The Impact of Residual Neuromuscular Blockade, Oversedation, and Hypothermia on Adverse Respiratory Events in a Postanesthetic Care Unit: A Prospective Study of Prevalence, Predictors, and Outcomes

Stewart, Paul A. MBBS, FANZCA*†; Liang, Sophie S. BSc (Adv), GStat, MBBS (Hons), MMed (Clin Epi)‡§; Li, Qiushuang Susan MBBS; Huang, Min Li BMedSci (Hons), MBBS; Bilgin, Ayse B. BEng, MBA, MMaths, PhD, PostGradDipHE#; Kim, Dukyeon BSc (Adv)*; Phillips, Stephanie BMed, FANZCA, FRCA*†

doi: 10.1213/ANE.0000000000001513
Anesthetic Pharmacology: Original Clinical Research Report
Free

BACKGROUND: Residual neuromuscular blockade (RNMB) has been linked to adverse respiratory events (AREs) in the postanesthetic care unit (PACU). However, these events are often not attributed to RNMB by anesthesiologists because they may also be precipitated by other factors including obstructive sleep apnea, opioids, or hypnotic agents. Many anesthesiologists believe RNMB occurs infrequently and is rarely associated with adverse outcomes. This study evaluated the prevalence and predictors of RNMB and AREs.

METHODS: This prospective cohort study included 599 adult patients undergoing general anesthesia who received neuromuscular blocking agents. Baseline demographic, surgical, and anesthetic variables were collected. RNMB was defined as a train-of-four ratio below 0.90 measured by electromyography on admission to the PACU. AREs were defined based on the modified Murphy’s criteria.

RESULTS: RNMB was present in 186 patients (31% [95% confidence interval (CI), 27%–35%]) on admission to the PACU. One or more AREs were experienced by 97 patients (16% [95% CI 13–19]). AREs were more frequent in patients with RNMB (21% vs 14%, P = .033). RNMB was significantly associated with age (adjusted relative risk [RR], 1.17 [95% CI, 1.06–1.29] per 10-year increase), type of operation (adjusted RR, 0.59 [95% CI, 0.34–0.99] for laparoscopic surgery compared with open abdominal surgery), and duration of operation (adjusted RR, 0.59 [95% CI, 0.39–0.86] for ≥90 minutes compared with <90 minutes). Using multivariate logistic regression, AREs were found to be independently associated with decreased level of consciousness (adjusted RR, 4.76 [95% CI, 1.49–6.76] for unrousable/unconscious compared with alert/awake) and lower core temperature (adjusted RR, 1.43 [95% CI, 1.04–1.92] per 1°C decrease). Although univariate analysis found a significant association between AREs and RNMB, the significance became borderline after adjusting for other covariates (adjusted RR, 1.46 [95% CI, 0.99–2.08]).

CONCLUSIONS: The prevalence of RNMB in the PACU was >30%. Older age, open abdominal surgery, and duration of operation <90 minutes were associated with increased risk of RNMB in our patients. Our RR estimate for AREs was highest for depressed level of consciousness. When AREs occur in the PACU, potentially preventable causes including RNMB, hypothermia, and reduced level of consciousness should be readily identified and treated appropriately. Delaying extubation until the patient is awake and responsive may reduce AREs.

From the *Sydney Adventist Hospital Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia; Department of Anaesthetics, Sydney Adventist Hospital, Wahroonga, New South Wales, Australia; School of Medicine, University of Western Sydney, New South Wales, Australia; §Blacktown Hospital, Blacktown, New South Wales, Australia; Queen Elizabeth Hospital, Adelaide, South Australia, Australia; Concord Repatriation General Hospital, New South Wales, Australia; and #Department of Statistics, Macquarie University, New South Wales, Australia.

Accepted for publication June 27, 2016.

Funding: This study was supported by the Jackson Rees Research Grant from the Australian Society of Anaesthestists, the Australasian Research Institute, and the Sydney Medical School Summer Research Scholarship Program. The Datex–Ohmeda EMG E-NMT equipment was loaned by GE Healthcare Australia. Merck Sharp and Dohme provided an unrestricted educational grant.

This report was previously presented, in part, at the 2013 Annual Scientific Meeting of the Australian and New Zealand College of Anaesthetists Perth, Western Australia, Australia, and the full patient complement and analysis was presented at the Australian Society of Anaesthetists National 72nd Scientific Conference, Canberra, Australian Capital Territory, Australia, September 2013. It was awarded an Australian Society of Anaesthetists/Smiths Medical Award.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Paul Stewart, MBBS, FANZCA, PO Box 82, Wahroonga, NSW, Australia 2076. Address e-mail to hypnos1@tpg.com.au.

Nondepolarizing neuromuscular blocking agents (ND-NMBAs) provide optimal conditions for tracheal intubation and surgery. However, when their effects persist after extubation, this residual neuromuscular blockade (RNMB) places patients at an increased risk of adverse respiratory events (AREs). These include upper airway obstruction, decreased pulmonary function, impaired pharyngeal reflexes and muscle coordination, increased risk of aspiration, impaired hypoxic ventilatory response, and increased morbidity and mortality.1–6

Since 2006, the prevalence of RNMB, defined currently as a train-of-four (TOF) ratio <0.9 using mechanomyography or electromyography (EMG), has been reported to be between 30% and 60%.4,7 However, quantitative neuromuscular function monitoring is uncommon during anesthesia and in postanesthetic care units (PACUs).8,9

In contrast to RNMB, the contribution of a decreased level of consciousness to upper airway obstruction and respiratory distress is widely appreciated. Awake extubation of patients is generally considered safer as the return of airway tone, reflexes, and respiratory drive allows the patient to maintain their own airway.

The aim of this study was to assess the prevalence and predictors of RNMB and AREs in our PACU. We hypothesized that in the setting of our anesthetic practice, there is a high prevalence of RNMB in the PACU and that these patients are at an increased risk of AREs.

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METHODS

This prospective cohort study received approval from the Sydney Adventist Hospital Human Research Ethics Committee (HREC 00141:028/2011), and informed verbal consent was obtained from all patients. All anesthesiologists were aware of the study, but no change in their usual anesthetic practice was requested. Adult patients requiring ND-NMBA for surgery were assessed for eligibility to participate in the study. Patients were excluded if they did not provide consent, were unable to be assessed with TOF ratio monitoring within 5 minutes of admission to the PACU, received a depolarizing muscle relaxant, or had procedures or conditions that prevented or may alter TOF ratio measurement. Conditions and procedures that were excluded from TOF ratio measurement included allergies to the surface electrode adhesive, patients with neuromuscular disease, and surgical procedures that prevented access on the sites where electrodes would be positioned.

Recruitment occurred between 8 am and 8 pm on weekdays during the study period and depended on the availability of monitoring equipment and study investigators. Patients admitted directly to the intensive care unit postoperatively were not included in the study.

The following baseline demographic variables were collected: age, sex, weight, height, and American Society of Anesthesiologists physical status score. Operative variables collected included type and duration of the operation. Anesthetic variables collected included anesthesia technique, type of ND-NMBA used, reversal of neuromuscular blockade, and use of intraoperative neuromuscular function monitoring.

On admission to the PACU, standard patient care was administered by trained and experienced nursing staff. TOF ratio monitoring using EMG (NMT-EMG, software 891647-2.0, Datex-Ohmeda, Helsinki, Finland) at the abductor digiti minimi muscle commenced within 5 minutes of admission to the PACU. Red Dot Ag/AgCl paediatric Micropore backed Electrodes (3M, St. Paul, MN) were placed on the arm without the intravenous line after skin preparation in accordance with current recommendations (Figure 1).10,11 TOF ratios were obtained using an initial 30-mA stimulus at 2 Hz and 200 µs in duration. The current strength was increased if the EMG waveform did not have a smooth biphasic profile with a well-defined upward deflection.10,11 If this did not improve the waveform, the electrodes were repositioned. TOF ratios were measured every 20 seconds until 2 measurements were within 5% of each other.

Figure 1.

Figure 1.

RNMB was defined as a TOF ratio <0.90. EMG is considered by many to be a clinical gold standard for TOF ratio monitoring because of its high precision and equivalence to mechanomyography during the late phase of recovery.12–18 If RNMB was present on admission to the PACU, neuromuscular function monitoring was repeated every 15 minutes until the TOF ratio was maintained at 0.90 or above.

Table 1.

Table 1.

Trained and experienced nursing staff monitored and recorded AREs based on the modified Murphy’s criteria within 15 minutes of admission to the PACU (Table 1).3,19 The original criteria based on the administration of oxygen at 3 l/min through nasal speculum were modified to 6 l/min through facemask to accommodate local practice in our PACU. Additional data collected in the PACU included level of consciousness on arrival, core and peripheral temperature, respiratory rate, oxygen delivery mode and flow, oxygen saturation, airway support, and posture. The classification of the level of consciousness was assessed as awake and alert, responsive to verbal commands, or unresponsive to verbal commands.

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Statistical Analysis

All analysis was performed using the statistical software R (version 2.14.2, R Foundation for Statistical Computing, Vienna, Austria) and Stata (version 13.1, StataCorp, College Station, TX). At the commencement of our study, there were no previous trials or cohort studies in the literature that report the association between RNMB and AREs. As such, we lacked previous data to use as a basis for sample size calculation for our primary outcome of the association between RNMB and AREs. Therefore, we were unable to do sample size calculations before undertaking the study. Where data for baseline characteristics were missing, we reported the number of available observations. The prevalence of RNMB and AREs was reported as percentages with the 95% confidence intervals (CIs). Continuous baseline variables were reported as mean ± standard deviation or median (interquartile range [IQR]) and compared using Student t test or Wilcoxon rank sum test. Categorical baseline variables were reported as frequency (percentage) and compared using χ2 test or Fisher exact test. All tests were predefined in the statistical analysis plan to be 2 sided with significance level α = .05 unless stated otherwise. Adjustments for multiple comparisons were not undertaken.

Predictors of RNMB and AREs were modeled using multivariate logistic regression analysis. Baseline variables with univariate P < .25 were chosen as candidate variables for the initial multivariate logistic regression model. Candidate variables with the largest nonsignificant P values were eliminated one at a time by stepwise backward selection. Candidate variables with confounding effects (elimination results in >20% change to other coefficients or affects the significance level of other covariates) were retained. Stepwise forward selection was then applied to verify that the previously eliminated variables were not significant. Collinearity and interaction effects were examined and confirmed to be absent. Goodness of fit of the final multivariate logistic models was assessed using the Hosmer-Lemeshow test. Odds ratios (ORs) were obtained from the final logistic regression model, and relative risks (RRs) were approximated from adjusted ORs using the method proposed by Zhang and Yu.20

OR and RRs are 2 similar measures used to measure the strength of association of an “exposure” variable (eg, RNMB) and an “outcome” variable (eg, AREs), and both measures have null values of 1 because both are ratio statistics. OR is the ratio of the “odds” of an event in the exposed group versus the unexposed group, and “odds” are defined as chance of success divided by chance of failure. Conversely, RR is the ratio of “risks,” which are defined as chance of success only. Therefore, RR is more intuitive to interpret than OR; “RR of 5” is the same as saying that “those in the exposed group have 5 times the risk or chance of having the outcome event as those who do not have the exposure.” When event rates are small, OR and RR tend to be very similar, and so the more mathematically convenient OR is often used to approximate RR.a

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RESULTS

Patient Characteristics

During the study period, 599 eligible patients treated by 81 anesthesiologists participated in the study. One anesthesiologist declined neuromuscular function monitoring in the PACU for their patients. The TOF ratio could not be obtained in 1 patient because of technical difficulty.

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Residual Neuromuscular Blockade

RNMB (TOF ratio <0.90) was present in 186 patients (31% [95% CI, 27%–35%]) on admission to the PACU. The TOF ratio was <0.70 in 78 (13%), between 0.70 and 0.79 in 41 (7%), and between 0.80 and 0.89 in 67 (11%). TOF ratios ranged from 0.14 to 1.0, with median of 0.96 and IQR of 0.14. The median time to neuromuscular function recovery (TOF ratio, >0.90) in these patients with RNMB was 15 minutes (IQR, 15–30 minutes).

Baseline demographic and clinical characteristics of the patients according to RNMB on admission to the PACU are shown in Table 2. The type (P < .0001) and duration (P = .0014) of the operation and the use of reversal agent (P = .042) significantly differed between patients with and without RNMB in univariate analysis.

Table 2.

Table 2.

Table 3.

Table 3.

Table 3 shows the final multivariate logistic regression model for RNMB. RNMB was significantly associated with age (adjusted RR, 1.17 [95% CI, 1.06–1.29] per 10-year increase). Compared with patients undergoing open abdominal surgery, those undergoing laparoscopic abdominal procedures (adjusted RR, 0.59 [95% CI, 0.34–0.99]), orthopedic or spinal procedures (adjusted RR, 0.14 [95% CI, 0.06–0.30]), ear, nose, and throat or dental procedures (adjusted RR, 0.24 [95% CI, 0.09–0.61]), urologic or gynecologic procedures (adjusted RR, 0.34 [95% CI, 0.14–0.78]), or other procedures (adjusted RR, 0.37 [95% CI, 0.21–0.65]) had significantly lower risk of RNMB. RNMB was significantly less likely to be associated with operations lasting 90 minutes or longer (adjusted RR, 0.59 [95% CI, 0.39–0.86]).b

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Adverse Respiratory Events

In the PACU, 97 patients (16% [13%–19%]) experienced at least 1 ARE, including 25 patients (26%) who experienced multiple AREs. The most common ARE was upper airway obstruction (78%), followed by respiratory distress or impending ventilatory failure (14%), mild to moderate hypoxemia (12%), respiratory or airway muscle weakness (10%), inability to breathe deeply (10%), severe hypoxemia (9%), need for assisted ventilation (3%), and pulmonary aspiration after tracheal extubation (1%). A total of 13.8% with a TOF ratio of ≥0.9, 23.1% with a TOF ratio in the range 0.7 to 0.89, and 18% of patients with a TOF ratio <0.7 experienced ARE. Difference in the proportions between TOF ratio 0.7 to 0.89 and TOF ratio <0.7 was not significant (P = .50).

Baseline characteristics and PACU admission variables according to AREs are shown in Table 4. RNMB (P = .028), core temperature (P < .0001), and level of consciousness (P < .0001) on admission to the PACU were significantly associated with AREs in the PACU.

Table 4.

Table 4.

Of the 186 patients who had RNMB on admission to the PACU, 39 patients (21% [16%–28%]) experienced AREs. Specifically, 12 of 67 (18%) had TOF ratios between 0.8 and 0.89, 13 of 41 (32%) had TOF ratios between 0.7 and 0.79, and 14 of 78 (18%) had TOF ratios <0.7. In contrast, of the 413 patients who did not have RNMB on admission to the PACU, only 57 (14% [11–18%] experienced AREs (P = .033; Figure 2).

Figure 2.

Figure 2.

Table 5.

Table 5.

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.

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DISCUSSION

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.

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CONCLUSIONS

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.

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DISCLOSURES

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.

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FOOTNOTES

aBonita R, Beaglehole R, Kjellstrom T. Basic Epidemiology. 2nd ed. World Health Organisation; 2006:46 and 192. Available at: http://apps.who.int/iris/bitstream/10665/43541/1/9241547073_eng.pdf.

bHosmer–Lemeshow test P value was .47.

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