Residual Neuromuscular Blockade and Adverse ... - Springer Link

Curr Anesthesiol Rep (2016) 6:178–184 DOI 10.1007/s40140-016-0151-z

NEUROMUSCULAR BLOCKADE (GS MURPHY, SECTION EDITOR)

Residual Neuromuscular Blockade and Adverse Postoperative Outcomes: An Update Aaron F. Kopman1,2

Published online: 19 March 2016 Springer Science + Business Media New York 2016

Abstract Residual weakness in our post-anesthesia-careunits (PACU) following the intra-operative administration of non-depolarizing neuromuscular blocking agents continues to be a frequent and usually unrecognized occurrence. If satisfactory recovery from these drugs is defined as a train-of-four ratio (TOF) of 0.90 or greater, probably not less than 30 % of patients fail to achieve this level of recovery upon arrival in the PACU. While most health young individuals will tolerate TOF values of 0.70 with no serious sequelae, this is not true of all patients. The elderly and patients with pre-existing conditions such as COPD, asthma, sleep apnea, obesity, and muscle or neurological disease may not be so fortunate. Anesthesia and surgery in the absence of muscle relaxant administration still cause major reductions in pulmonary reserve. The additional combination of residual block, and the contributing factors listed above are a recipe for post-op pulmonary complications. Keywords Neuromuscular Postoperative residual neuromuscular block Neostigmine Sugammadex Monitoring Train-of-four

This article is part of the Topical Collection on Neuromuscular Blockade. & Aaron F. Kopman [email protected] 1

70 East 10th Street, Apt. 17F, New York, NY 10003, USA

2

Present Address: 19970 Sawgrass Lane, Unit 4102, Boca Raton, FL 33434, USA

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Preface In 2013 Sorin Brull and I co-authored a review in this journal entitled: ‘‘Is postoperative residual neuromuscular block associated with adverse clinical outcomes? What is the evidence?’’ [1]. In this paper, we supplied considerable background material on such subjects as monitoring neuromuscular function in the operating room, the train-offour (TOF) ratio as a surrogate marker of postoperative residual neuromuscular block (PORB), the incidence of PORB in our post-anesthesia-care-units (PACU), contributing factors to PORB, and the clinical consequences of residual block in the PACU. This review is available on the Current Anesthesiology Reports website at no cost and I urge the reader to familiarize themselves with his material as an adjunct to this chapter. The present review is intended as a supplement, not a replacement, to the 2013 review. In this update, I will focus on material which was published after our prior study went to press; basically, material which became available in the years 2012–2015. I will only occasionally refer the reader to classic studies, reviews, or editorials which we cited in the 2013 paper. Another recent (2014) review also available from Current Anesthesiology Reports by Farhan et al. [2] provides additional relevant information and is highly recommended.

Introduction Is PORB a significant public health problem? A 2010 survey [3] of practices among anesthesiologists toward the intra-operative management of neuromuscular block reveals what appear to be inconsistent and contradictory ideas. While 78 % of anesthetists from the USA state that the answer to this question is yes, only 11 % of almost

Curr Anesthesiol Rep (2016) 6:178–184

1800 responders claim to have actually observed a patient exhibiting significant residual block in his/her operating room or PACU, and the vast majority thought that the incidence of significant episodes of PORB in their institutions was \1.0 %. Objective analysis of the incidence of PORB paints a very different picture. For many years, recovery to a TOF ratio of 0.70 was considered indicative of adequate return of neuromuscular function [4]. This is no longer the case. The modern definition of satisfactory neuromuscular recovery is a TOF ratio of C0.90 at the adductor pollicis muscle [5], and to exclude residual paralysis reliably when using acceleromyography, a TOF recovery to 1.0 is considered mandatory by many [6]. Unfortunately PORB continues to be a common but usually unrecognized clinical occurrence in our PACU (see Table 1). These current data are totally compatible with older information that the overall incidence of TOF ratios \0.90 on arrival in the PACU is still probably in the range of 25–40 %, and 10–15 % of patients are admitted with TOF ratios \0.70! [7–9]. While there is evidence to suggest that when a strong and consistent educational effort is made at the departmental level to encourage the use of neuromuscular monitoring that the incidence of PORB can be significantly reduced [10••, 11••, 12], unfortunately dedicated mentors who are willing to persist in changing local practices are few and far between. Perhaps, someday, when the use of selective reversal agents such as sugammadex becomes widely available and routinely administered, PORB will cease to be a common occurrence (see ‘‘Sugammadex and PORB’’ section below). In the interterm, the following question still has clinical relevance: Do minor degrees of residual block (TOF ratios

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of 0.40 or greater) have adverse respiratory consequences? The answer is decidedly yes [1, 13–16]. The remainder of this chapter will focus on relevant information published from 2012 until the present (the autumn of 2015).

Kumar et al While residual block of modest extent (TOF ratios of 0.60–0.70) is associated with signs and symptoms of clinical weakness [23], most young healthy subjects are unlikely to suffer significant morbidity at this level of block. In Heier’s study [16] of young volunteers, none experienced airway obstruction or arterial oxygen desaturation at a normalized TOF ratio of 0.40 even though vital capacity was reduced by 26 ± 7 % (8–41 %) at this level of block. However, a recent paper by Kumar et al. [24••] reminds us that this margin of safety may not exist for many individuals. They point out that postoperative respiratory reserve may be diminished in various conditions. Patient factors such as obesity, pre-existing pulmonary, neurological or muscular disease, and surgical factors such as the site of incision, postoperative pain, and effects of residual anesthetics all may work to increase respiratory complications. The authors recruited 150 ASA 1–2 patients scheduled for elective surgeries lasting for less than 3 h. During preanesthesia evaluation, all the patients were familiarized with using a spirometer. Baseline forced vital capacity (FVC-1) and peak expiratory flow rate (PEF) were measured in all subjects. Anesthesia was maintained with isoflurane/N2O plus incremental fentanyl. Patients were

Table 1 Recent (2013–2015) studies of the incidence of PORB on arrival in the PACU References

TOF results

Remarks

Fortier et al. [17]

66 % \ 0.90; 20 % \ 0.70

Canada. N = 207. Normalized acceleromyograph (AMG). Reversal with neostigmine

Norton et al. [18•]

30 % \ 0.90

Portugal. N = 202. Reversal with neostigmine as per individual anesthetist. Displayed AMG value in PACU

Esteves et al. [19•]

26 % \ 0.90

Portugal. N = 350. Displayed AMG value in PACU. Reversal with neostigmine in 66 % of patients

Pietraszewski et al. [20]

In patients [65 years of age, 44 % had TOF ratios \0.70. In younger patients this value was still 20 %

Poland. N = 415. Spontaneous recovery. No intra-op neuromuscular monitoring

Brueckmann et al. [21••]

Post sugammadex 0 of 74 had a TOF \ 0.90 Post neostigmine 33 of 76 (43 %) had a TOF less than 0.90

USA. N = 150. Half sugammadex. Half neostigmine. Displayed AMG value measured in PACU. Intra-op NM monitoring not mandatory in neostigmine group

Cammu et al. [22]

TOF ratios \0.90: spontaneous recovery 15 %, neostigmine 15 %, sugammadex 2 %

Belgium. Spontaneous recovery N = 441. Neostigmine reversal N = 139. Sugammadex N = 44

Todd et al. [11••]

TOF \ 0.90 = \15 %

USA. Data represent a 50 % reduction in PORB in the 3 years following the implementation of quantitative neuromuscular monitoring in this department

TOF \ 0.80 = 5 %

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randomized to receive either atracurium, vecuronium, or rocuronium, and dosage was left to the discretion of the individual clinician. Neuromuscular monitors were not employed intra-op. All patients received neostigmine 0.05 mg/kg at the end of surgery. On arrival in the PACU (and every 5 min thereafter), patients’ TOF ratios were measured with a TOF-Watch monitor. As soon as the patient could co-operate, pulmonary functions (PFT) tests were repeated. On admission to the PACU, 57 % had a TOF ratio less than 0.90 (defined by the authors as residual neuromuscular block; RNMB). This persisted in 39 patients (26 %) at the time of PFT testing. There were no significant differences in any neuromuscular or pulmonary parameter between the three blockers administered. Even in the absence of RNMB (N = 111), average PEF values fell by 53 % and FVC-1 values by 38 %. When RNMB was present, these values were decreased by 62 and 51 %, respectively (P \ 0.01). Thus in patients with RNMB, there was a 21 % reduction in FVC and a 19 % reduction in PEF in the immediate postoperative period compared with patients who had completely recovered from neuromuscular blockade. The authors hypothesize that these small decrements imposed on already compromised pulmonary function may have adverse clinical consequences.

Post-op Pulmonary Complications: Predisposing Factors Gu¨ldner et al. [25] provide an excellent review of conditions (asthma, sleep apnea, COPD, etc.), which may predispose a patient to postoperative pulmonary complications (POPC). They go on to discuss how risk factors (other than residual neuromuscular block) may be modified to reduce the frequency of POPC. Similarly Brueckmann et al. [26] propose a method for predicting POPC using a simple 11-point score that can be used preoperatively to predict severe respiratory complications. These papers are useful supplements to the paper by Kumar et al. [24••].

The MGH Group In the 2012–2015 period, several studies emanating from the Dept. of Anesthesia at the Massachusetts General Hospital arrived at rather unexpected and controversial conclusions. Grosse-Sundrup et al. [27] found ‘‘The use of intermediate acting neuromuscular blocking agents during anesthesia was associated with an increased risk of clinically meaningful respiratory complications.’’ They submit that reversal of neuromuscular blockade using an acetylcholinesterase inhibitor at the end of surgery may increase a patient’s risk of

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developing clinically meaningful respiratory complications. Meyer et al. [28] go even further. They state ‘‘under the conditions studied neostigmine and qualitative neuromuscular transmission monitoring did not mitigate the increased risk of postoperative respiratory complications linked to the use of non-depolarizing neuromuscular blocking agents.’’ Sasaki et al. [29] reported that when given in high doses or unguided by neuromuscular transmission monitoring, neostigmine administration may be associated with an increased incidence of postoperative respiratory complications such as atelectasis. The rationale for these caveats was presumably based at least in part on the observation that when neostigmine is administered when non-depolarizing neuromuscular is minimal or absent that transient weakness and a decrement in the TOF ratio may follow [30–32]. A more comprehensive and balanced analysis of this research group’s findings came from McLean et al. in 2015 [33••]. It is this publication which in my opinion supersedes the group’s earlier assertions. They now conclude that ‘‘the proper use of neostigmine guided by neuromuscular transmission monitoring … can help eliminate postoperative respiratory complications associated with the use of neuromuscular blocking agents.’’ They add what is no doubt a sensible caveat. Neostigmine should not be administered until the TOF-count is two or more, and neostigmine dosage should be limited to B0.06 mg/kg. A recent publication from this research group is worth noting. Baumu¨ller et al. [34•] provide additional evidence that a TOF ratio of 0.90 at the adductor pollicis as measured by electromyography represents essentially full neuromuscular recovery. The authors administered either sugammadex 1.0 mg/kg or saline (N = 150 per group) to patients in their PACU who had measured TOF ratios C0.90 after recovering from anesthesia. Sugammadex did not improve subjects’ motor function or sense of well-being when compared with placebo. Finally, Sasaki et al. at MGH [35] provide an excellent review of the pathophysiology of postoperative respiratory muscle dysfunction; residual neuromuscular block is only part of the story. Standard perioperative medications (anesthetics, sedatives, and opioids), interventions (patient positioning, mechanical ventilation, and surgical trauma), and diseases (lung hyperinflation, obesity, and obstructive sleep apnea) are all part of the equation. The authors’ list of references is extensive (N = 228) and worthy of perusal.

Piccioni et al A study by Piccioni et al. [36•] combines elements of the Kumar [24••] and Baumu¨ller [34•] studies cited above. These authors studied 20 patients scheduled for major


abdominal surgery. On the day prior to surgery and just before induction of anesthesia control pulmonary function tests (PFT) were performed. These included FVC, FEV-1, and maximum inspiratory and expiratory pressures (MIP; MEP). Neuromuscular block was established with rocuronium, and anesthesia was maintained with desflurane 3–4 % inspired and ropivacaine via a thoracic epidural catheter. Desflurane was stopped at the end of surgery and spontaneous recovery from neuromuscular block was allowed until the TOF ratio as measured by a TOF-Watch monitor reached 1.0. If necessary, propofol was given while awaiting neuromuscular recovery. Patients were extubated as soon as possible after reaching a TOF ratio of 1.0. Ten minutes after extubation, PFTs were repeated. Patients then received either sugammadex 1.0 mg/kg or placebo. PFTs were again repeated in 5 and 20 min after the test drug. At no time were there statistical differences in pulmonary function between the sugammadex or placebo groups. At 20 min post the test drug MIP and MEP were still only at approximately 40 % of control values, and the FEV-1 and FVC were reduced by about 30–40 % from baseline. In as much as control acceleromyographic (AMG) TOF values exceed electromyographic (EMG) ratios by 0.10–0.15 [6, 37, 38], this study nicely confirms the observations of Baumu¨ller [34•]. A displayed (not normalized) AMG value of 1.0 or an EMG value of 0.90 represents full clinical recovery. The authors’ observations also nicely confirm those of Kumar [24••] and demonstrate that even in a best case scenario (pain relief via thoracic epidural anesthesia) that pulmonary function is measurably impaired following abdominal surgery even in the absence of residual neuromuscular block.

Ha˚rdemark Cedborg et al Elderly individuals are at increased risk for tracheal aspiration secondary to impaired pharyngeal function which results from an increased frequency of misdirected swallowing. An elegant paper by Ha˚rdemark Cedborg et al. [39••] reminds us that even very modest levels of residual block (TOF ratios of 0.70) may in healthy elderly individuals result in a even greater inability to protect the airway. Pharyngeal function and coordination of breathing and swallowing were assessed by manometry and videoradiography in 17 volunteers, mean age 73.5 years. After control recordings, rocuronium was administered to obtain steady-state TOF ratios of 0.70 and 0.80 followed by spontaneous recovery to greater than 0.90 as measured by mechanomyography. Pharyngeal dysfunction increased significantly at train-offour ratios 0.70 and 0.80, and swallowing showed a more

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severe degree of dysfunction during partial neuromuscular block. After recovery to train-of-four ratio of greater than 0.90, pharyngeal dysfunction was not significantly different from the control state. The authors stress the importance of avoiding PORB in the elderly.

Sugammadex and PORB The limitations of neostigmine as an antagonist of even moderate levels of non-depolarizing block (TOF-counts of 1–3) are well known [40–42]. Thus, until something better came along it seemed that the phenomenon of PORB would be an ever present reality. This forecast had to be modified in 2008 with the availability of sugammadex. For the first time anesthesiologists had the ability to rapidly antagonize even profound neuromuscular block (post-tetanic counts of 1–2) [43, 44]. There is now strong evidence that this drug when used with proper monitoring can significantly reduce and perhaps eliminate residual neuromuscular weakness in the postoperative period. A study of Brueckmann et al. [21••] shows what is possible. One hundred and fifty adult patients underwent abdominal surgery with rocuronium. They received by randomized allocation (N = 74 and 77 % respectively) sugammadex (2 or 4 mg/kg) or usual care (neostigmine/ glycopyrrolate, dosing per usual care practice) for reversal of neuromuscular blockade. Timing of reversal agent administration was based on the providers’ clinical judgment. A TOF-watch monitor was available intra-op to all clinicians and was used in the about 85 % of cases. The displayed TOF ratio was recorded on entry into the PACU. Forty-three percent of the usual care patients had TOF ratios \0.90. None of the patients reversed with sugammadex exhibited residual block. As reassuring as the above results are, it appears that no drug is totally fool proof. Kotake et al. [45•] provide evidence of this. This was a 2-stage, prospective, observational study conducted at five university-affiliated teaching hospitals in Japan. In the first stage, the intra-operative anesthetic management was at the discretion of the attending anesthesiologist who was unaware that the patient had been included in a study. Rocuronium was used to facilitate tracheal intubation, and increments of this drug were administered ‘‘as needed.’’ Depth of relaxation was estimated by clinical signs. When the attending anesthesiologist judged that there was adequate spontaneous recovery from neuromuscular blockade, neostigmine was administered in a dose deemed appropriate by the clinician. After tracheal extubation, a TOF-watch monitor was used to determine the TOF ratio prior to transfer to the PACU. The second stage of the study differed only in that sugammadex 2.0–4.0 mg/kg

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was used for reversal, the dose was based on clinical signs only. The interval between reversal and TOF measurements average about 12 ± 8 and 8 ± 4 min in the neostigmine and sugammadex groups, respectively. In the neostigmine group, 26 of 109 patients (24 %; 95 % CL 16–33) had TOF values \0.90 shortly after extubation. In the sugammadex group only 5 of 117 individuals (4.3 %; 95 % CL 1.7–9.4) had TOF values \0.90. Thus sugammadex is a highly effective antagonist of rocuronium. However, in the absence of at least conventional or qualitative intra-operative neuromuscular monitoring (to determine the recommended dose) it is not perfect. The upper value of the 95 % confidence limits in the sugammadex group suggests that as many as 9 % of subjects may have had TOF values less than 0.90 at extubation. It should also be remembered that an acceleromyographic TOF ratio of 0.90 may not represent full neuromuscular recovery. An excellent (although slightly dated; 2013) review of the clinical status of sugammadex by Schaller and Fink is a good starting place for an overview of the promise and caveats associated with this drug [46].

Conclusions In a recent Letter to the Editor, El Orbany [47] suggests that residual neuromuscular block should be considered a ‘‘Never Event.’’ That is, there should be a reasonable expectation on the part of patients, payors [sic], and the lay public that these events will not happen during the course of health care delivery [48]. Unfortunately, we have not yet reached this goal. A recent study from Brazil found that less than 15 % of anesthesiologists reported the frequent use of neuromuscular function monitors [49]. A survey from Australia and New Zealand report essentially identical (17 %) results [50]. These data are disheartening as the recipe for eliminating or at least markedly reducing the incidence of PORB is not a secret [51–54]. Monitoring is the key. Clinicians need to recognize that PORB is more common in their patients than they recognize and not all individuals will escape unscathed from this reality. Funding No funding was received for the preparation of this manuscript.

Compliance with Ethics Guidelines Conflict of Interest conflict of interest.

Aaron F. Kopman declares that he has no

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. Kopman AF, Brull SJ. Is postoperative residual neuromuscular block associated with adverse clinical outcomes? What is the evidence? Curr Anesthesiol Rep. 2013;3:114–21. 2. Farhan H, Moreno-Duarte I, McLean D, Eikermann M. Residual paralysis: does it influence outcome after ambulatory surgery? Curr Anesthesiol Rep. 2014;4:290–302. 3. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A survey of current neuromuscular practice in the United States and Europe. Anesth Analg. 2010;111:110–9. 4. Ali HH, Wilson RS, Savarese JJ, Kitz RJ. The effect of d-tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. Br J Anaesth. 1975;47:570–4. 5. Fuchs-Buder T, et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand. 2007;51:789–808. 6. Capron F, Alla F, Hottier C, Meistelman C, Fuchs-Buder T. Can acceleromyography detect low levels of residual paralysis?: a probability approach to detect a mechanomyographic train-offour ratio of 0.9. Anesthesiology. 2004;100:1119–24. 7. Maybauer DM, Geldner G, Blobner M, Puhringer F, Hofmockel R, Rex C, Wulf HF, Eberhart L, Arndt C, Eikermann M. Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaesthesia. 2007;62:12–7. 8. Yip PC, Hannam JA, Cameron AJ, Campbell D. Incidence of residual neuromuscular blockade in a post-anaesthetic care unit. Anaesth Intensive Care. 2010;38:91–5. 9. Hayes AH, et al. Postoperative residual block after intermediateacting neuromuscular blocking drugs. Anaesthesia. 2001;56:312–8. 10. •• Todd MM, Hindman BJ, King BJ. The implementation of quantitative electromyographic neuromuscular monitoring in an academic anesthesia department. Anesth Analg. 2014; 119:323–31. Since the introduction of department-wide quantitative neuromuscular blockade monitoring, the authors saw no PACU reintubations in appropriately monitored patients. However, use of EMG monitoring had a steep learning curve. 11. •• Todd MM, Hindman BJ. The implementation of quantitative electromyographic neuromuscular monitoring in an academic anesthesia department: follow-up observations. Anesth Analg. 2015;121:837–40. Implementation of universal electromyographic-based quantitative neuromuscular blockade monitoring required a sustained process of education along with repeated PACU surveys and feedback to providers. Nevertheless, this effort resulted in a significant reduction in the incidence of incompletely reversed patients in the PACU. 12. Baillard C, Clec’h C, Catineau J, Salhi F, Gehan G, Cupa M, Samara CM. Postoperative residual neuromuscular block: a survey of management. Br J Anaesth. 2005;95:622–6. 13. 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;28:842–8. 14. Berg H, Viby-Mogensen J, Roed J, Mortensen CR, Engbaek J, Skovgaard LT, Krintel JJ. Residual neuromuscular block is a risk


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