Anaesthesia 2018, 73, 1055–1066 doi:10.1111/anae.

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Editorial

Neostigmine-induced weakness: what are the facts?

M. Naguib1 and A. F. Kopman2

1 Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and
Staff Cleveland Clinic, Department of General Anesthesia, Cleveland, OH, USA
2 Clinical Professor of Anesthesiology (Retired), Weill Cornell Medical College, New York City, NY, USA

.................................................................................................................................................................
Correspondence to: M. Naguib
Email: naguibm@ccf.org
Keywords: adverse effects; muscle weakness; neostigmine; neuromuscular blockade
This editorial accompanies an article by Kent et al., Anaesthesia 2018; 73: 1079–89.

‘There is nothing more deceptive than an obvious
fact.’
—Sir Arthur Ignatius Conan Doyle (May 1859–July
1930)
In this issue of Anaesthesia, Kent et al. [1] report that
administration of neostigmine 2.5 mg (mean (SD) dose
35 (6) lg.kg 1
) plus glycopyrrolate 450 lg to a small
number of healthy volunteers, in the absence of a previ-
ously administered non-depolarising neuromuscular
blocker (NMB), resulted in manifestations of a depolaris-
ing neuromuscular block: muscle weakness, fasciculations
and multiple subjective symptoms such as diplopia and
dysphagia. These data appear to stand in marked con-
trast to the observations of a recent investigation by Mur-
phy et al. [2] whose findings could not have been more
different. In the latter study, the authors administered
1
neostigmine 40 lg.kg once the train-of-four (TOF)
ratio had spontaneously recovered to a value > 0.90
from an initial dose of rocuronium. Neostigmine was not
associated with any objective evidence of anti-
cholinesterase-induced muscle weakness, and was also
associated with decreased incidence of postoperative
diplopia [2].
Who should we believe, Kent or Murphy? The
answer is that both sets of observations are credible, but
the study of Kent probably has little or no clinical rele-
vance. 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.
This difference in response to neostigmine probably
is the result of continued receptor occupancy by the non-
depolarising NMB. Even when the TOF ratio approaches
unity following recovery from a non-depolarising block,
there is still a substantial degree of receptor occupancy at
the neuromuscular junction. Waud and Waud estimated
that at full return of the TOF ratio, 70–75% of postsynaptic
receptors are still occupied [3]. Kopman found that follow-
ing recovery to a TOF ratio of 0.95 post mivacurium
administration that the ED50 (the dose the caused 50%
reduction of twitch height) value for the relaxant was
decreased by 56% [4]. Thus, partial receptor occupancy
undoubtedly persists at a time when even objective
evidence (e.g. the TOF ratio) is indicative of full recovery
of neuromuscular function. It appears that this receptor
occupancy provides a protective effect from the
depolarising actions of excess acetylcholine.
The notion that neostigmine administration at a time
when spontaneous clinical recovery from non-depolarising
block is almost complete may have adverse clinical conse-
quences has been disputed [2, 5–7]. Murphy’s observations
are not unique. Choi [8] and Schaller [9] report successful
reversal of residual neuromuscular block at a TOF ratio of
0.50 with neostigmine ≤ 40 lg.kg 1
and others [10, 11]
found that even lower doses of neostigmine (10–30 lg.kg 1)
are required at TOF ratios of 0.60. Furthermore, Harper
et al. [12] administered a large dose of neostigmine
(0.08 mg.kg 1) to 10 subjects at recovery of the first twitch
height (T1) to 40–50% of control (TOF count = 4 with fade).
They concluded that “. . .despite monitoring the EMG for at
least 30 min after administration of neostigmine, we were
unable to demonstrate “neostigmine block” which would

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Anaesthesia 2018, 73, 1055–1066
have been revealed either as prolonged antagonism or as
recurarisation” [12].
Thus, the effect of an anticholinesterase on neuro-
muscular transmission seems to be dependent on
whether or not a non-depolarising NMB is also present
at the neuromuscular junction [13, 14]. In a curarised
muscle, anticholinesterases increase the end-plate poten-
tial and the underlying end-plate current [15]. Conversely,
in the absence of a non-depolarising NMB, anti-
cholinesterases at concentrations that almost completely
inhibit the acetylcholinesterase, depress the amplitude
and the half-time of the end-plate current are depressed
[16].
Although Kent’s observations clearly demonstrate
that neostigmine can produce a depolarising block in the
absence of a preceding dose of a non-depolarising NMB,
we are concerned that the casual reader will misinterpret
his results. Neostigmine-induced decrements in neuro-
muscular function should almost never occur clinically.
First, in the peri-operative setting, there is no reason to
administer neostigmine except to antagonise a previously
administered non-depolarising NMB. Second, unless
neostigmine is given several hours following the non-
depolarising NMB, the ‘protective’ effect of the first drug
will still be in effect. A study by Caldwell [17] is instruc-
1 3. Waud BE, Waud DR. The relation between the response to
tive. He administered vecuronium 0.10 mg.kg to
groups of 10 patients under nitrous oxide/oxygen/
isoflurane anaesthesia and allowed spontaneous recov-
ery; then, after 1 h, 2 h, 3 h and 4 h, he administered
1
neostigmine 40 lg.kg . At 1 h, 2 h or 3 h, neostigmine
was always followed by an increase in the TOF ratio. At
4 h, he was able to demonstrate a slight transient
decrease in the mean TOF ratio (initial value 0.91, 0.83
10 min later with return to a value of 0.95 at the end of
the surgical procedure). In an additional 10 patients
antagonised with only 20 lg.kg 1
at 4 h, no decrease in
the TOF ratio was observed. The duration of this ‘window
of protection’ may vary to some degree depending on
the NMB administered. It is likely to be longer following
a traditional long-acting drug such as pancuronium and
shorter after a drug such as mivacurium.
Kent et al. conclude that their study provides support
for mandatory quantitative neuromuscular monitoring [18,
19] before the administration of neostigmine, so that
reversal is not attempted if spontaneous recovery from
neuromuscular blockade has already occurred. We have
no argument with this statement [20], but unfortunately
many, if not most, anaesthetists still do not have access
to objective neuromuscular monitors. What is the clinician
to do when they can no longer detect fade on TOF
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Editorial
stimulation at the adductor pollicis muscle when using a
conventional peripheral nerve stimulator following
spontaneous recovery from a non-depolarising NMB?
Available evidence suggests that the prudent course of
action is to still administer a small (≤ 30 lg.kg 1
) dose of
neostigmine. Unless many hours have passed since the
last dose of the non-depolarising NMB was given, anxiety
regarding paradoxical neostigmine-induced weakness is
misplaced and unnecessary.
Acknowledgements
MN and AK contributed equally to the writing of this edi-
torial. MN has served as a consultant for GE Healthcare in
2018. No other external funding or competing interests
declared.
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