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Neostigmine-induced weakness after sugammadex

Last post 06 Nov 2018, 9:17 PM by Naguib Mohamed. 1 replies.
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  •  17 Oct 2018, 1:19 AM 2671

    Neostigmine-induced weakness after sugammadex

    We would like to challenge Naguib and Kopman's editorial assertion [1] that Kent et al.'s study on neostigmine-induced weakness in awake volunteers [2] 'probably has little or no clinical relevance’. 

    In clinical practice, we have observed that, when neostigmine 50-70 mcg.kg-1 has partially reversed a patient’s neuromuscular blockade, the subsequent administration of sugammadex 200mg as a ‘rescue’ agent can result in a paradoxical reduction in the train-of-four (TOF) ratio. Complete recovery of neuromuscular function to a TOF ratio > 0.9 may then take an extended and variable period. This phenomenon has also been reported in a study of non-surgical volunteers, where neostigmine and sugammadex resulted in a reduction of diaphragmatic activity [3]. 

    A possible explanation for this observation is consistent with Kent et al.’s findings. Administration of sugammadex 200mg results in near complete removal of rocuronium or vecuronium from the neuromuscular junction, thus also removing the protective effect of partial receptor occupancy on the depolarising actions of excess acetylcholine. The resulting neostigmine-induced block only recedes as the drug is metabolised and acetylcholine levels return to normal. 

    A further observation is that resultant neuromuscular block demonstrates characteristic fade on the TOF response after the administration of sugammadex. A possible explanation for this is that the large amount of intrasynaptic acetylcholine made available after high-dose neostigmine administration may result in a desensitisation block, similar to a phase II block after high-dose suxamethonium. In Kent et al.’s study, we note that no fade was noted, even in patients who received two doses of neostigmine with a mean total dose of 69 mcg.kg-1. The reason for this discrepancy is unclear, but may be a result of partial metabolism of the first dose of neostigmine given.

    The recommended dose of sugammadex for reversing a minimal neuromuscular block (defined as a TOF ratio of 0.4-0.9) is 0.25-0.5 mg.kg-1[4]. The dose used in the cases we have observed was 200mg, approximately 2-4 mg.kg-1. It is tempting to speculate that a reduced dose of sugammadex would not have resulted in a paradoxical increase in neuromuscular blockade. This observation warrants confirmation in the context of a formal clinical trial. 

     

    J. A. Szental

    D. Bramley

    Western Health,

    Melbourne, Australia.

    Email: Joshua.Szental@wh.org.au

     

    No external funding and no competing interests declared.

     

    References 

    1.      Naguib M, Kopman AF. Neostigmine-induced weakness: what are the facts? Anaesthesia 2018; 73: 1055-66.

    2.      Kent NB, Liang SS, Phillips S, et al. Therapeutic doses of neostigmine, depolarising neuromuscular blockade and muscle weakness in awake volunteers; A double blind, placebo controlled, randomised volunteer study. Anaesthesia 2018; 73: 1079-90.

    3.      Cammu G, Schepens T, De Neve N, Wildemeersch D, Foubert L, Jorens PG. Diaphragmatic and intercostal electromyographic activity during neostigmine, sugammadex and neostigmine–sugammadex-enhanced recovery after neuromuscular blockade. European Journal of Anaesthesiology 2017; 34: 8-15.

    4.      Brull SJ, Kopman AF. Current status of neuromuscular reversal and monitoring: challenges and opportunities. Anesthesiology 2017; 126: 173-90.

     

  •  06 Nov 2018, 9:17 PM 2683 in reply to 2671

    Neostigmine-induced weakness after sugammadex: a reply

     We thank Drs. Szental and Bramley for their informative and well-reasoned letter. In our editorial [1], we stated that “Kent’s observations clearly demonstrate that neostigmine can produce a depolarising block in the absence of a preceding dose of a non-depolarising neuromuscular block (NMB).” However, we also suggested that “in the peri-operative setting, neostigmine is never administered in the absence of a preceding dose of a non-depolarising NMB. Kent’s observations appear to be valid only when neostigmine administration is not preceded by a non-depolarising NMB.”

    Drs. Szental and Bramley have described what appears to be a valid exception to our latter comment. As these authors note 200 mg of sugammadex may result in complete removal of a steroidal based relaxant from the neuromuscular junction. Thus a large dose of neostigmine (50-70 µg.kg-1) administered earlier may indeed result in a depolarising block in what is now an unprotected neuromuscular receptor.

    While the details of Drs. Szental and Bramley’s cases are not reported, their clinical observations make theoretical sense. They remind us that “reading the fine print” can be important. Neostigmine has clear limitations in its ability to reverse even moderate neuromuscular block. Even at a train-of-four count (TOF) of four no dose of neostigmine can guarantee return to a TOF ratio of 0.90 within 10 minutes in 95% of subjects [2, 3]. Thus, what is a clinician to do when he/she wishes to antagonize residual block at a TOF count of 1, 2, or 3? Alternative #1, simply administer an appropriate dose of sugammadex. If one elects to administer neostigmine (and results are unsatisfactory) one option is simply to wait, but this solution may be impractical. If the clinician chooses to “finish the job “with sugammadex this must be done cautiously and hopefully with quantitative monitoring. As the authors suggest, doses as small as 0.25 to 0.05 mg.kg-1 may well be sufficient.

    In conclusion, we stand by our initial statement. In the usual clinical setting, depolarizing block following neostigmine-induced antagonism of residual block is not to be anticipated.

    A. Kopman

    Weill Cornell Medical College,

    New York, NY, USA.

    M. Naguib

    Cleveland Clinic,

    Cleveland, OH, USA.

    Email: naguibm@ccf.org

     

    MN has served as a consultant for GE Healthcare in 2018. No other external funding or competing interests declared.

     

    References

    1. Naguib M, Kopman AF. Neostigmine-induced weakness: what are the facts? Anaesthesia 2018; 73: 1055-7.

    2. Kirkegaard H, Heier T, Caldwell JE. Efficacy of tactile-guided reversal from cisatracurium-induced neuromuscular block. Anesthesiology 2002; 96: 45-50.

    3. Kaufhold N, Schaller SJ, Stauble CG, Baumuller E, Ulm K, Blobner M, Fink H. Sugammadex and neostigmine dose-finding study for reversal of residual neuromuscular block at a train-of-four ratio of 0.2 (SUNDRO20)dagger. British Journal of Anaesthesia 2016; 116: 233-40

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