Residual neuromuscular blockade (RNMB) continues to be a common but usually undetected occurrence in the early postoperative period.1 Residual paralysis in the postanaesthesia care unit (PACU) may contribute to morbidity in patients recovering from general anaesthesia and is a risk factor for postoperative adverse outcomes.2–4 Impaired pharyngeal function, weakness of upper airway muscles and decreased ventilatory response to hypoxaemia resulting from residual paralysis may potentially increase the risks of aspiration, hypoxaemia, airway obstruction, the need for reintubation and pulmonary complications.5–8
RNMB is a potentially preventable patient safety problem and it is important to find ways to reduce its incidence. The use of neuromuscular blocking (NMB) agents of intermediate action, intraoperative neuromuscular monitoring and reversal of neuromuscular block have been described as factors which contribute to the reduction but not elimination of RNMB.5,6,9 Therefore, proper intraoperative monitoring of neuromuscular function is essential to prevent or at least reduce the incidence of RNMB. For many years, an adductor pollicis train-of-four (TOF) ratio of 0.7 was considered sufficient to exclude postoperative residual curarisation.10 However, in recent years, several reports have documented that a TOF ratio of 0.7 does not guarantee sufficient neuromuscular recovery and the current general consensus is that to exclude clinically significant postoperative residual curarisation, the TOF ratio should be at least 0.9.8,11,12 Quantitative neuromuscular monitoring methods, such as acceleromyography, provide more objective data on neuromuscular transmission and improve detection of neuromuscular blockade in comparison with visual or tactile evaluation of the TOF response.13,14 Although quantitative neuromuscular function monitoring is frequently recommended, many anaesthesiologists base their evaluation of the recovery of neuromuscular function in their daily practice on clinical data, which are subjective.15
Although the introduction of intermediate-acting muscle relaxants such as vecuronium and atracurium has helped to reduce its incidence, RNMB continues to occur.16 In a French study of 526 patients who received a single dose of vecuronium, rocuronium or atracurium to facilitate tracheal intubation and received no more relaxant thereafter, TOF ratios less than 0.7 and 0.9 were observed in 16 and 45% of the patients on arrival in the PACU, respectively.5 In an audit of RNMB from Australasia, 31% of patients exhibited RNMB on entry to the PACU (TOF ratio <0.9).17 In a meta-analysis of 3375 patients, the pooled incidence of postoperative residual curarisation was 41.3% for intermediate-acting muscle relaxants with a TOF ratio less than 0.9.18 In a review of studies published since 2000 reported by Murphy and Brull,1 the incidence of RNMB defined as TOF ratio less than 0.9 and measured with acceleromyography varied widely between 3.5 and 83%.
Until now, there has been no large-scale study about the frequency of RNMB in Portugal. Therefore, a study was designed to determine the incidence of incomplete postoperative neuromuscular recovery from anaesthesia at PACUs in Portuguese hospitals.
Between July and November 2010, all consecutive adult patients undergoing different types of elective surgical procedures requiring general anaesthesia with NMB agents at various public Portuguese hospitals were eligible to participate in a multicentre observational study. The primary objective of the study was to assess the incidence of postoperative RNMB, defined by a TOF ratio less than 0.9, on arrival in the PACU. The secondary objective of the study was to assess the association between comorbidities, administered medication and the TOF ratio on arrival at the PACU. The study was conducted in daily practice conditions. Centres were selected according to the following considerations: adequate representation of the Portuguese mainland territory, relevant number of annual procedures with general anaesthesia and a walking time between the operating room and the PACU of less than 10 min.
The study protocol was approved by the Ethics Committee of the participating hospitals: Hospital Santo António, Porto (085- CES; Chairman Professor Maria Luisa Bernardo) on 22 June 2010, Hospitais da Universidade de Coimbra (097-CES; Chairman Professor Jose J. S. Barros) on 6 July 2010, Hospital São João (12122; Chairman Professor Manuel Pestana) on 30 June 2010, Centro Hospitalar de Vila Nova de Gaia (CA; Chairman Professor Helena Figueiredo) on 27 May 2010, Hospital Santa Maria (PCA 0606, Chairman Professor João Lobo Antunes) on 20 May 2010, Hospital Pedro Hispano (CA; Chairman Professor José Alberto Rodrigues Silva) on 5 July 2010, Hospital Fernando da Fonseca (CA; Chairman: Professor Vitor Gil) on 28 June 2010, Centro Hospitalar de Coimbra (1358/SEC; Chairman Prof Alice Torcato) on 9 September 2010, and all patients gave written informed consent. The study was also registered at ClinicalTrials.gov registry (Identifier: NCT01181349).
The design of the study included a first cross-sectional evaluation of RNMB upon arrival at the PACU, and a second retrospective study period in which data from the patient's medical record were collected after hospital discharge. Male and female patients aged 18 years or older, scheduled for elective surgery who received a non-depolarising NMB agents during general anaesthesia were included in the study. Exclusion criteria were surgical operation on an emergency basis or the need for reoperation during the same hospital admission.
The choice of drugs used for premedication and anaesthesia as well as the use of neuromuscular transmission monitoring was left to the discretion of the anaesthesiologist in charge of the patient. On arrival in the PACU, an independent anaesthesiologist who was not involved in the anaesthetic procedure checked all the inclusion and exclusion criteria and confirmed that the patient had signed the consent form. If the patient met the inclusion criteria, neuromuscular transmission monitoring was immediately performed, after standard monitoring and oxygen supplementation had been started. In all the patients, 40-mA TOF stimulation (four pulses of 0.2 ms in duration, at a frequency of 2 Hz) was performed at the ulnar nerve every 15 s via two surface electrodes. The evoked responses at the thumb were measured by the TOF-Watch SX acceleromyograph (Organon Teknika, Boxtel, the Netherlands). The TOF-Watch was used in an uncalibrated mode. Three consecutive TOF measurements (separated by 15 s) were obtained and the average of the three values was recorded. If measurements differed by more than 20%, additional TOF measurements were not obtained and the patient was excluded from the study. Patients were also excluded if three TOF measurements could not be obtained. On arrival at the PACU, heart rate, blood pressure and skin temperature (volar surface of the forearm) were recorded.
Patients were categorised into two groups on the basis of TOF data; TOF ratios at least 0.9 and less than 0.9 were assessed as complete and incomplete neuromuscular recovery following general anaesthesia, respectively.
For each patient, the following data were recorded after hospital discharge: demographics (age, sex) and anthropometric (height, weight) data, clinical history, surgical diagnosis, American Society of Anesthesiologists (ASA) physical status, perioperative data (medication used during operation, neuromuscular blocker and blockade reversal agents), time between date of enrolment and date of hospital discharge, comorbidities, adverse events and vital status at discharge. Postoperative events were grouped into infectious and parasitic; endocrine, nutrition, metabolic and immunological; blood and blood-forming organs; circulatory system; respiratory system; digestive system; genitourinary system; skin and subcutaneous system; musculoskeletal system and connective tissue; and ill-defined conditions. Type of surgery was not recorded.
Assuming that the Portuguese population undergoing surgical procedures under general anaesthesia in the next year would be approximately 100 000 individuals and according to an incidence of objective evidence of incomplete neuromuscular recovery on arriving at the PACU of 36%, with a margin error of 5% and a confidence interval (CI) of 95%, a sample size of 350 patients was required. The primary endpoint of the study was the number of patients who arrive at the PACU with a TOF ratio less than 0.9. Secondary endpoints were the association between comorbidities, administered medication and a TOF ratio less than 0.9 in the PACU. The full analysis set (FAS) population that included all treated patients who met the inclusion criteria was used for analysis. The χ2 test or Fisher's exact test were used for the comparison of variables between the groups of incomplete and complete neuromuscular recovery. Data were analysed with the Statistical Package for the Social Sciences (SPSS; version 15.0) statistical software programme. Categorical variables are expressed as frequency and percentages, and continuous variables as mean and standard deviation (SD) or median and range (minimum, maximum) according to the distribution of data. Statistical significance was set at P less than 0.05.
A total of 385 patients were recruited from eight hospitals but 35 did not meet the inclusion criteria (emergency surgery or reoperation during the same hospital admission) and were excluded. Therefore, the study population consisted of 350 patients, 134 men and 216 women, with a mean age of 54.3 ± 15.9 years (range: 19 to 91 years) undergoing elective surgery. The mean body temperature was 32.4 ± 2.6°C, the mean heart rate 71.3 ± 12.7 beats per min, the SBP 134.6 ± 21.8 mmHg and the DBP 74.0 ± 13.0 mmHg.
The three consecutive TOF measurements showed a high rate of agreement (96.6% concurrence) and in no case did differences between TOF measurements exceed 20%, so that the estimation of the RNMB incidence was based on the whole study population of 350 patients. In relation to the primary endpoint of the study, 91 patients showed a TOF ratio less than 0.9 on arrival in the PACU, with an incidence of RNMB of 26% (95% CI 21 to 31%).
Data collected after hospital discharge included a mean weight of 72.5 ± 15.1 kg, mean height of 163.5 ± 7.8 cm and a mean BMI of 27.2 ± 5.8 kg m−2. A total of 20.3% of patients were included in ASA physical status category 1, 59.1% in category 2, 20.3% in category 3 and 0.3% in category 4. The most frequent comorbidities included diseases of the circulatory system in 48% of the cases, endocrine, metabolic and/or immunological disorders in 40.3%, neoplasms in 29.9%, digestive system in 18.3%, respiratory system in 17.3%, genitourinary system in 16%, musculoskeletal system and/or connective tissue in 9.8%, mental disorders in 7.8% and neurological diseases in 7.5%.
Details of intraoperative data are shown in Table 1. The drugs most frequently used as neuromuscular blockers were rocuronium and cisatracurium. A total of 66.6% of patients (n = 233) received a reversal agent; 97% received neostigmine and only 3% received sugammadex. The incidence of RNMB in patients receiving reversal agents was 30% (95% CI 25 to 37%). The mean total doses (intubation and maintenance) of these drugs are shown in Table 2. Other drugs most frequently used were propofol, fentanyl, paracetamol and atropine (Table 1). As shown in Fig. 1, there were no statistically significant differences in the occurrence of RNMB according to the neuromuscular blocker used, although higher percentages were observed for cisatracurium and vecuronium compared with atracurium and rocuronium. Incomplete neuromuscular recovery was significantly more frequent among patients who received a blockade reversal agent (30.5 vs. 17.1%, P = 0.01). Incomplete neuromuscular recovery was more frequent in patients given propofol for maintenance of anaesthesia (60/229, 26.2%) than in those who received sevoflurane (four of 28, 14.3%), but the number of patients with RNMB exposed to sevoflurane (n = 4) was too small for statistical testing.
As shown in Fig. 2, postoperative events appeared to be more frequent among patients with incomplete neuromuscular recovery than in those with complete neuromuscular recovery, but the differences were not statistically significant (P = 0.223). According to the categories of postoperative events, the frequency of RNMB in the group of patients with complications related to the circulatory and respiratory systems was 4.4% each, to the genitourinary system, infections and ill-defined conditions 2.2% each, and to the digestive system, skin and subcutaneous tissue, and endocrine, metabolic and immunological disorders, 1.1% each.
The occurrence of adverse events was low (2.9%, 10/350). Adverse events were classified as severe in 20% of cases and moderate in 40% (Table 3). In the seven patients treated with sugammadex, adverse events were not observed. The median length of hospital stay was 5 (interquartile range 2 to 8) days. The final outcome was assessed in 344 patients. The in-hospital mortality rate was 0.3% (one of 344 patients). The patient who died was an 80-year-old woman who developed acute respiratory distress syndrome and septic shock; the cause of death was considered by the investigators possibly to be related to surgery. The TOF ratio of this patient in the PACU was at least 0.9.
The present study was carried out in conditions of routine daily practice and, for the first time, provides data on the incidence of incomplete neuromuscular recovery in the PACU in Portuguese hospitals. Although other studies on this topic from different countries have been published,3,5,17 it is important to have local data because differences do exist between countries and over time. This was an observational trial designed to assess the incidence of RNMB as the primary endpoint but endpoints did not include evaluating the rationale for using neuromuscular block reversal agents or the time since the last dose of neuromuscular blocker. It should be noted that the purpose of the study was not to identify risk factors associated with residual neuromuscular block. Also, data on the timing of repeated administration of NMB agents or of the administration of reversal agents have not been recorded, so that the potential impact of neostigmine on the incidence of complications cannot be evaluated.
For the purpose of the present study, RNMB was defined as a TOF ratio less than 0.9 measured objectively by acceleromyography. In a clinical series of 350 patients undergoing elective surgical procedures at eight public hospitals which can be considered representative of the country because of their geographical location and the number of patients attending annually, the incidence of RNMB was 26%. This percentage is within the range reported in similar studies published in the literature,1,5,9,17,19 and highlights the dimension of the problem of incomplete neuromuscular recovery in the PACU in our country.
Murphy et al.20 assessed the incidence and severity of residual neuromuscular block at the time of tracheal extubation and found that 88% had a TOF ratio less than 0.9, suggesting that complete recovery from neuromuscular blockade is rarely present at the time of tracheal extubation. At the time of arrival in the PACU, the percentage of patients with a TOF ratio less than 0.9 was significantly lower (32%; P <0.001). The same authors21 examined the effect of choice of NMB drug (pancuronium vs. rocuronium) on postoperative recovery times and associated adverse outcomes in patients undergoing orthopaedic surgical procedures. Patients were randomised to receive pancuronium or rocuronium immediately before entering the operating room. On arrival in the PACU, TOF fade ratios were measured using acceleromyography. Patients assigned to receive pancuronium intraoperatively were more likely to exhibit symptoms of muscle weakness and develop hypoxaemia, and required more time to meet discharge criteria. In our study, there were no statistically significant differences in the occurrence of RNMB according to the neuromuscular blocker used. It has been shown that the use of intermediate-duration NMB drugs decreases the incidence of postoperative residual curarisation8,21,22, and also the incidence of postoperative respiratory complications.2 However, the use of intermediate-duration blocking drugs is also associated with incomplete neuromuscular recovery. In our study, the incidence of RNMB in relation to the different muscle relaxants ranged between 20.8 and 32.4%. Cammu et al.23 reported that the incidence of residual paralysis, as determined by TOF ratio less than 0.9, was 38% in outpatients and 47% in inpatients. The lower incidence of residual paralysis in outpatients was thought to be due to the use of short-acting neuromuscular blockers (e.g. mivacurium). The durations of surgical procedures were not assessed in our study, so it is not possible to determine whether short surgical procedures were associated with higher incidences of postoperative residual curarisation when using intermediate-duration NMB drugs.8 Additionally, the time interval between the end of surgery and TOF measurement in the PACU was not evaluated, so its potential impact on RNMB was not determined.
Incomplete neuromuscular recovery was significantly more frequent among patients who received a reversal agent (30.5%) compared with those who did not (17.1%). In the large majority of the patients, neostigmine was administered. Many practitioners avoid the use of reversal drugs because of their potential side-effects (e.g. increased incidence of nausea and vomiting). However, systematic reviews of published studies report that the incidence of postoperative nausea and vomiting and the need for antiemetics do not increase with the use of neostigmine.24,25 Using appropriate doses of reversal drugs matched for the degree of blockade should avoid the side-effects of reversal drugs. To avoid postoperative RNMB, there is a need for a change in clinicians’ attitudes towards monitoring and reversal in routine anaesthetic practice. Baillard et al.9 evaluated changes of perioperative neuromuscular block management between 1995 and 2004 and quantified the incidence of incomplete neuromuscular recovery rate. Quantitative measurements and reversal of neuromuscular block in the operating room increased from 2 to 60% and from 6 to 42%, respectively (P < 0.001). During the same time, the incidence of RNMB (defined as TOF ratio < 0.9) decreased from 62 to 3% (P < 0.001). Moreover, the use of objective neuromuscular monitoring and/or anticholinesterase drugs was less common in patients with inadequate neuromuscular recovery.
However, a significantly higher incidence of RNMB in patients who have received a reversal agent can be explained on a speculative basis. The use of reversal agents is related to the more rapid reversal of the effects of neuromuscular blockade and, therefore, it would be expected that patients who were reversed would have less residual curarisation than those who were not. The possible explanation for these findings could be that patients to whom no reversal agent was given had not received a NMB agent for a long time, or had been given very small doses of these agents, and that there was sufficient spontaneous reversal of neuromuscular at the end of anaesthesia block to avoid RNMB. Another reason could be that neuromuscular monitoring had been used during anaesthesia and that this had demonstrated that there was no need for a reversal agent at the time of extubation. However, several factors that influence RNMB were not evaluated in this study, such as time of administration of the last dose of neuromuscular agents, the duration of operation and the use of objective neuromuscular blockade monitoring during surgery.
A higher incidence of RNMB was observed in patients who had been anaesthetised with propofol compared with sevoflurane. It is known that halogenated inhaled anaesthetic agents prolong the effects, and negatively affect the reversal, of NMB agents compared with propofol,26 but this did not appear to be the case in our study. However, the number of patients anaesthetised with sevoflurane vs. propofol was very small and precludes definitive conclusions.
Peripheral nerve stimulation has been adopted widely because it facilitates quantification of the neuromuscular response to muscle relaxants without the need for comparison with a control response. However, current evidence has demonstrated that frequently used clinical tests of neuromuscular function (such as head lift or hand grip) cannot reliably exclude the presence of residual paralysis. It is very difficult to visually or manually evaluate a TOF ratio with sufficient certainty to exclude residual blockade; once the TOF ratio exceeds 0.4, most clinicians are unable to detect that any fade exists. Furthermore, the effect of qualitative monitoring on postoperative residual paralysis remains controversial. A recent meta-analysis could not demonstrate that the use of intraoperative evaluation of the TOF response using a conventional nerve stimulator influenced the frequency of postoperative residual curarisation.18 In contrast, there is strong evidence that acceleromyography (quantitative) monitoring improves detection of small degrees (TOF ratios >0.6) of residual blockade.14 Capron et al.27 observed that an acceleromyographic TOF ratio of 0.97 corresponded to a mechanomyographic TOF ratio of 0.9, and concluded that TOF ratios assessed by acceleromyography must recover to 1 (rather than 0.9) to reliably exclude residual neuromuscular block.
We found that postoperative events (mainly related to the circulatory and respiratory systems) appeared to be more frequent among patients with RNMB than in those with complete neuromuscular recovery, although the difference was not statistically significant. These findings are consistent with the consequences of residual paralysis. Because residual paralysis can increase postoperative morbidity, there is increasing emphasis on its prevention.3,5,7
In summary, although the information presented is not new, this observational study provides for the first time an estimate of RNMB in Portugal, contributing to increased knowledge of this event in routine clinical practice. The incidence of incomplete neuromuscular recovery of 26%, and 30.5% in patients who received a reversal agent, confirms that RNMB is relatively frequent in the postoperative period and calls attention to the dimension of this problem in Portuguese hospitals. This was an observational study and although some interesting differences were observed, it is not possible to determine causality. However, the study reflects real world conditions, which is an important contribution to the available evidence. The present results may also contribute to a better understanding of the impact of incomplete neuromuscular recovery in the PACU on comorbidities and complications after surgery.
Assistance with the study: the authors thank other colleagues and nurses who contributed by obtaining informed consent and collecting data on the PACU, Merck Sharp & Dohme Lda (MSD Portugal), Medical Affairs Department staff for contributions to the study design and implementation, and Marta Pulido MD, freelance editor, for writing and editorial assistance.
Financial support and sponsorship: the study was sponsored by MSD Portugal. The fees for medical writing were supported by MSD Portugal.
Conflicts of interest: SE has an advisory role and has received honoraria from MSD Portugal and MS has had an advisory role for MSD Portugal. For the remaining authors, none were declared.
1. Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg
2. Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand
3. Murphy GS, Szokol JW, Marymont JH, et al. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg
4. Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology
5. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology
6. Murphy GS. Residual neuromuscular blockade: incidence, assessment and relevance in the postoperative period. Minerva Anestesiol
7. Eriksson LI. Residual neuromuscular blockade. Anaesthesist
2000; 49 (Suppl 1):S18–S19.
8. Claudius C, Garvey LH, Viby-Mogensen J. The undesirable effects of neuromuscular blocking drugs. Anaesthesia
2009; 64 (Suppl 1):10–21.
9. Baillard C, Clec’h C, Catineau J, et al. Postoperative residual neuromuscular block: a survey of management. Br J Anaesth
10. Ali HH, Utting JE, Gray TC. Quantitative assessment of residual antidepolarizing block. II. Br J Anaesth
11. Viby-Mogensen J. Postoperative residual curarization and evidence-based anaesthesia. Br J Anaesth
12. Kopman AF. Undetected residual neuromuscular block has consequences. Anesthesiology
13. 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
14. Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. Part II: methods to reduce the risk of residual weakness. Anesth Analg
15. Brull SJ, Naguib M, Miller RD. Residual neuromuscular block: rediscovering the obvious. Anesth Analg
16. 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
17. Yip PC, Hannam JA, Cameron AJD, Campbell D. Incidence of neuromuscular blockade in a postanaesthetic care unit. Anaesth Intensive Care
18. Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and postoperative residual curarisation: a meta-analysis. Br J Anaesth
19. Maybauer DM, Geldner G, Blobner M, et al. Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaesthesia
20. Murphy GS, Szokol JW, Marymont JH, et al. Residual paralysis at the time of tracheal extubation. Anesth Analg
21. Murphy GS, Szokol JW, Franklin M, et al. Postanesthesia care unit recovery times and neuromuscular blocking drugs: a prospective study of orthopedic surgical patients randomized to receive pancuronium or rocuronium. Anesth Analg
22. Murphy GS, Szokol JW, Marymont JH, et al. Recovery of neuromuscular function after cardiac surgery: pancuronium versus rocuronium. Anesth Analg
23. Cammu G, De Witte J, De Veylder J, et al. Postoperative residual paralysis in outpatients versus inpatients. Anesth Analg
24. Cheng CR, Sessler DI, Apfel CC. Does neostigmine administration produce a clinically important increase in postoperative nausea and vomiting? Anesth Analg
25. Tramèr MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and risk of residual paralysis. A systematic review. Br J Anaesth
26. Lowry DW, Mirakhur RK, McCarthy GJ, et al. Neuromuscular effects of rocuronium during sevoflurane, isoflurane, and intravenous anesthesia. Anesth Analg
27. Capron F, Alla F, Hottier C, et al. Can acceleromyography detect low levels of residual paralysis? A probability approach to detect a mechanomyographic train-of-four ratio of 0.9. Anesthesiology