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Reevaluation and update on efficacy and safety

of neostigmine for reversal of neuromuscular
blockade
This article was published in the following Dove Press journal:
Therapeutics and Clinical Risk Management

Jie Luo Abstract: Postoperative residual neuromuscular block is a serious threat which endangers
Shuting Chen the patient safety. Neostigmine has been the most commonly used anticholinesterase for
Su Min the pharmacological reversal of neuromuscular blockade. Although newer agents have been
Lihua Peng introduced recently, neostigmine has some irreplaceable advantages, including broad-spectrum
reversal of all nondepolarizing neuromuscular blocking drugs, low cost, and availability of more
Department of Anesthesiology, The
First Affiliated Hospital of Chongqing related data for clinical practice to refer to. Neostigmine is also noticed to have some drawbacks,
Medical University, Chongqing 400016, such as the inability to reverse profound and deep blockade, potential induction of muscle
China
weakness, cardiovascular adverse effects, and so on. Data on the usage of neostigmine in the
geriatric and the pediatric population are still insufficient. Some discrepancies are observed in
the results from previous studies which need further investigation. However, recent studies offer
some renewed information. Regarding both efficacy and safety, the key for successful reversal
of neuromuscular blockade is to use neostigmine “appropriately,” optimizing the dosage and
timing of administration under close monitoring.
Keywords: postoperative residual neuromuscular block, neuromuscular reversal, anticholin-
esterase, postanesthesia care, postoperative complication

Introduction
According to the report of the Lancet Commission on Global Surgery, Global Surgery
2030, about 30% of the global burden of disease can be treated with surgeries.1 General
anesthesia is a vital component for many major surgeries. Postoperative residual
neuromuscular block (PRNB), defined as the train-of-four (TOF) ratio (TOFR) ,0.9,
has remained a problem with general anesthesia for surgeries. When reversal agents
were not administered, the incidence of PRNB could be as high as 37%–82%.2–4
After the routine use of anticholinesterase reversal agents, a relatively reduced PRNB
incidence of 20%–40% at arrival of the postanesthesia care unit (PACU) has been
observed.5 PRNB is associated with an increased risk of postoperative pneumonia,
coma, and mortality,6,7 and appropriate antagonism benefits patients.8 Anticholinest-
erases have been the only available agents for neuromuscular reversal during the past
six decades before sugammadex was introduced.8 Having been clinically used since
Correspondence: Su Min 1931, neostigmine is the most common antagonist for neuromuscular blockade with the
Department of Anesthesiology, The First
Affiliated Hospital of Chongqing Medical advantages of broad-spectrum reversal of all nondepolarizing neuromuscular blocking
University, No 1 Youyi Road, Yuzhong drugs (NMBDs), low cost, and availability of more related data for clinical practice
District, Chongqing 400016, China
Tel/fax +86 23 8901 1068
to refer to. Although sugammadex has emerged as a strong competitor, the cost–
Email ms89011068@163.com benefit analysis results of its routine administration are still considerably uncertain.9–11

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Luo et al Dovepress

Indeed, benefit of sugammadex in moderate block has not of a study in 2018, although only a small dose of rocuronium
been fully certified; still, its benefit lies in its speed of reversal, (ED95) was given for tracheal intubation and the anesthesia
intensity of reversal, and most importantly in its ability to duration was relatively long (an average of 163 minutes),
reverse deep block, even in the case of failed intuition. This there were still 21% patients who had residual paresis at the
review aims to offer a reevaluation and update of both the end of surgery.2 PRNB endangers patients’ safety, for which
clinical efficacy and safety of neostigmine usage for reversal the routine administration of antagonists is beneficial for
of neuromuscular blockade based on more recent studies. reducing the risk of incomplete neuromuscular recovery.17
There is evidence that in the absence of routine reversal, the
Pharmacology PRNB incidence and associated complications markedly
As an anticholinesterase, neostigmine mainly inhibits increased.4,18,19 It is recommended that there should be a
the breakdown of acetylcholine, increases acetylcholine routine administration of anticholinesterases in all patients
in the neuromuscular junction, and enhances the avail- who receive intraoperative nondepolarizing NMBDs for
ability of acetylcholine to compete with NMBDs. The diminishing PRNB, unless full recovery is confirmed with
metabolism of all the three clinically available anti- quantitative monitoring. 17,20,21 However, the actual use
cholinesterases (neostigmine, edrophonium, and pyri- of reversal agents varies widely with different countries,
dostigmine) is influenced by renal function, age, body anesthesia types, and individual physician’s preferences,3,16
temperature, intraoperative anesthetics used, NMBDs type and only 18% of European and 34% of American anesthesi-
and administration route, and the acid–alkali condition.8 The ologists routinely use reverse muscle relaxants.22
distribution half-life (T1/2α), elimination half-life (T1/2β), and Some physicians tend to overestimate the adverse
total plasma clearance of neostigmine are 3.4 minutes, 77 effects of anticholinesterases to outweigh the risks caused
minutes, and 9.1 mL/kg/min, respectively.12,13 Both the effec- by PRNB, and caution against the routine administration of
tive duration and efficacy are related to the type of NMBDs, anticholinesterases postoperatively.23–26 Since the safety of
concomitant anesthetics, the neuromuscular reversal target, routine administration of neostigmine was reported in 1959,
and the depth of muscular relaxation when neostigmine is the routine usage of neostigmine has been a continuing topic.
administered. A newly designed administration route, trans- A few studies found that the incidence of residual paralysis
dermal electroporation, of neostigmine elicited equivalent did not change with the administration of neostigmine, and
action as the intravenous one.14 neostigmine was associated with an increased incidence
One of the most noticeable drawback of neostigmine is of postoperative atelectasis, which questions the potential
its inability to reverse profound and deep blockade, which of neostigmine in improving neuromuscular recovery.27–29
results from a plateau reached when acetylcholinesterase However, a recent study in over 11,000 patients indicated that
inhibition is near 100%, and the maximal concentration of neostigmine could reduce the respiratory complications and
acetylcholine is achieved with increasing neostigmine dose 30-day mortality which were associated with NMBDs.The
not parallelly producing an additional effect (ie, the ceiling most common caution has been the reduction in TOFR, muscle
effect). The blockade reversal duration of neostigmine weakness, and adverse respiratory events when neostigmine
may be correlated with this effect as well.15 Moreover, the is given in the absence of neuromuscular blockade, but a few
potential for neostigmine to rapidly recover is limited as other studies found that neostigmine administration after
it cannot instantaneously and completely antagonize, and nearly full neuromuscular recovery could have no adverse
takes 10 minutes to achieve the peak effect.16 The muscle effect and result in no clinically important muscle weakness.30
weakness caused by neostigmine when administered after a The causes of these above discrepancies between results of
full recovery from neuromuscular blockade may be due to the different studies include variations in the therapeutic range,
increased sensitivities of muscles to overloaded acetylcholine appropriate dosing and timing, and some limitations of incon-
and the desensitization of the receptors. sistent definition of some indices. For example, reintubation
was measured within 7 days postoperatively in a study, which
could not be attributed to the use of neostigmine.26 There-
Administration for neuromuscular fore, further large-scale prospective studies with comparable
blockade reversal designs and controlled factors are required, especially for
The necessities of routine usage determining neostigmine’s appropriate dosing and timing.31
It was not until 1945 that the importance of neuromuscular Most anesthesiologists deem that antagonism of neuro-
blockade reversal had been realized. According to the results muscular blockade is not necessary if fade is absent when

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Dovepress Recent update on neostigmine for reversal of neuromuscular blockade

assessed with a monitor, there is no muscle weakness with not more effective in shortening the reversal duration when
clinical examinations or the time interval since administration administered during deep muscle relaxation.40
of the last dose of intermediate-acting NMBDs exceeds The exact optimal dosage of neostigmine varies mainly
60 minutes. However, there are evidence that the postop- based on the extent of spontaneous recovery at the time of
erative risks of some patients increased: even 2 or more administration, the half-life of the NMBDs used, and the con-
hours after a two time ED95 dose of intermediate-acting comitant anesthetics, which are yet to be defined for all levels
NMBD, the TOFR of 37% patients was ,0.9.3 The causes of neuromuscular block. In a few other studies, there was no
of underestimated usage of neostigmine in these patients may difference between 0.035 and 0.05 mg/kg doses in time to
include insensitivities of the nerve stimulator assessment and full recovery for 0.5 mg/kg rocuronium block at T1 of at least
evaluation based on the clinical signs for detecting those 10%. The speed of acceleration of recovery when administered
with TOFRs of 0.4–0.9, who actually experience a residual 5 minutes after administration of rocuronium (0.4 mg/kg) also
neuromuscular blockade. In practice, if a nondepolarizing did not differ between 0.03 and 0.05 mg/kg neostigmine, and
NMBD was given in a single small dose (one or two times 0.03, 0.04, and 0.055 mg/kg neostigmine doses demonstrated
ED95) and/or .2 hours had elapsed since the administration, very similar time course of effect.41,42 It was considered
the benefit of neostigmine should be balanced with potential that 2.5 mg neostigmine was an unnecessarily large dose
risks cautiously.2 In fact, neostigmine may not be capable of to antagonize the effects of atracurium and vecuronium,
preventing residual paralysis if administered incorrectly, and if .20% recovery of T1/T0 had already occurred when
the administration must be guided by, at a minimum, subjec- administered.37,43 Moreover, in the same situation, 1.25 mg
tive (more preferably, objective) monitoring.5,32 neostigmine was effective as well, and 0.625 mg accelerated
recovery after atracurium (although not vecuronium).43 It was
Dosing of neostigmine administration calculated that 0.034 mg/kg neostigmine was required to
In the 1940s, neostigmine was reported to be given “seldomly” recover 95% of patients from a TOFR of 0.5–0.9 or higher
in doses of up to 5 mg for the reversal of tubocurarine within 5 minutes.44 As little as 0.02 mg/kg neostigmine could
(0.4 mg/kg) for abdominal surgery.33 During the early period, be sufficient for a successful reversal of shallow atracurium
neostigmine was used at a dose of 1.25–2.5 mg per patient, block (TOFR of 0.4) within 10 minutes, and 0.01 mg/kg was
but later in 1979 it was reported that 2.5 mg was not effective for TOFR of 0.6–0.9.36,45
enough.34,35 A dose–effect curve was generated demon- Data also suggested that neostigmine may be used in
strating the dose-dependent effect of neostigmine and the excessive doses than necessary to antagonize the effects of
ceiling effect.36 It was theoretically proved that the larger high-dose NMBDs.46 However, neostigmine was associated
the dosage, the faster the effects and more complete the with a dose-dependent increase in the risk of postoperative
reversal. As compared with 0, 0.01, and 0.02 mg/kg doses, respiratory complications, and high doses of neostigmine
0.04 mg/kg neostigmine was associated with the shortest time did not improve respiratory safety.27,47 Normal doses of
to reach a TOFR of 1.0 from 0.5 for the reversal of shallow neostigmine may produce muscle weakness in the situation
neuromuscular blockade with rocuronium or cisatracurium.30 of low degrees of residual neuromuscular blockade (ie, a
The administration of 0.02, 0.04, and 0.08 mg/kg doses TOFR .0.4), and evidence demonstrates that neostigmine
of neostigmine for reversal of atracurium at T1 values of doses over 0.06 mg/kg may lead to transient muscular
40%–50% of control resulted in the median recovery times weakness.26,27,47,48 Considering the possible muscular weak-
to a TOF $0.7 of 4.5, 3.0, and 2.3 minutes, respectively.37 ness when administered for shallow blocks and the dose
A dose of 0.05 mg/kg neostigmine could reduce the duration dependence of its adverse cardiovascular effects, relatively
of recovery to at least half as compared to the spontaneous lower dosage of neostigmine may be beneficial when
recovery duration after rocuronium administration.38 In fact, recovery is almost complete. Routine administration of
even 0.07 mg/kg neostigmine could not reliably reverse reduced doses of neostigmine (0.01–0.02 mg/kg) even when
a residual neuromuscular block of a TOFR of 0.2 within no fade was felt after TOF or double-burst stimulation can
10 minutes.39 Moreover, it was not possible to reach a be beneficial for preventing shallow, but potentially harmful,
TOFR of 0.9 within 30 minutes in all patients, regardless of degrees of residual paralysis.31,32 Decreasing the dose of anti-
the number of tactile responses presenting at neostigmine cholinesterase may reduce adverse effects, and one prudent
(0.07 mg/kg) administration.15 When used at a higher dose of trend to use neostigmine is with as low a dose as is necessary
up to 0.08 mg/kg, neostigmine could not bring more benefits, to produce effective reversal effects and minimize the side
and a second dose after a single dose of 0.07 mg/kg was effects.41 However, based on the lack of compelling evidence

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of the efficacy of neostigmine doses as small as 0.01 mg/kg, Anticholinesterase agents produce neuromuscular weakness
the opponent opinion considers that doses of ,0.02 mg/kg and tetanic or TOF fade if there was not a previous expo-
are not recommended for light or minimal block.5 TOF sure to NMBDs, and dose-related collapse of upper airway
monitoring should be used to evaluate the possible need for muscles may occur, which can be diminished if NMBDs are
an additional dose of neostigmine. present (even in small doses).48,55
The interaction of anesthesia with halogenated agents There have been contrary results from different studies.
should be taken into consideration as well. Most inhalational A study showed that a second dose of neostigmine
anesthetic agents potentiate neuromuscular block. When (0.07 mg/kg) after the same first dose administered for
0.07 mg/kg neostigmine was administered on reappearance reversal of vecuronium neither hastened nor prolonged the
of the first tactile TOF response for reversal of rocuronium recovery.40 Similarly, a recent study indicated that neo-
(0.60 mg/kg), the median recovery time to a TOFR of 0.9 stigmine administration after spontaneous recovery to a
was longer under sevoflurane anesthesia (28.6 minutes) TOFR of 0.9–1.0 was not associated with clinical evidence
than propofol anesthesia (8.6 minutes).49 It was found that of anticholinesterase-induced muscle weakness, and small
neostigmine at doses $0.02 mg/kg could offset the poten- increases in TOFR were even observed.2 The causes which
tiating effect of sevoflurane on neuromuscular blockades, may contribute to these inconsistent results include the differ-
and isoflurane was found to offset the decreasing effects on ences in NMBDs used, monitoring technology, or measurable
TOFR of neostigmine (0.02 mg/kg) which was administered indices, whether neostigmine was administrated after the
when TOFR was 0.88 or 0.92 at 2 or 4 hours after a single termination of inhalational anesthesia, and so on.
dose of vecuronium. Another concern of timing of neostigmine is that the
administration is “too early.” There were no advantages in
Timing of neostigmine administration giving neostigmine early when deep blockade was present,
One concern of timing of neostigmine is that the admin- even in doses .0.05 mg/kg, and 0.07 mg/kg neostigmine
istration is “too late”. It has been held for a long time that would also delay the reversal duration when given during
if neostigmine is given after full neuromuscular recovery, deep muscle relaxation.14,56 Comparison of the effects of
muscle weakness may be induced theoretically. It was found neostigmine 0.06 mg/kg administered at different depths of
in a report in 1980 that in addition to 2.5 mg neostigmine blockade indicated that the total recovery time could not be
administered for antagonism of neuromuscular blockade, shortened by early usage of neostigmine and attempted antag-
the administration of a second dose (2.5 mg) depressed the onism from intense blockade following atracurium infusion
peak tetanic contraction and reestablished tetanic fade, but offered no clinical advantages.57 The total time to recovery
this study design does not reflect the current routine clinical was found to be the same whether neostigmine (0.07 mg/kg)
practice.23,50 Another study reported similar reintroduction of was administered 15 minutes after vecuronium (0.1 mg/kg)
neuromuscular blockade with a second dose of neostigmine or it was given when T1 had recovered to 10% of control.40
(2.5 mg) after the first dose at 1 hour after administration The median recovery time to a TOFR of 0.9 with 0.07 mg/kg
of vecuronium.51 A later study also indicated that a second neostigmine for reversal of rocuronium at a posttetanic count
dose of neostigmine 2.5 mg diminished tetanic height and of 1–2 (deep block) was 49 minutes, and similarly situation
increased tetanic fade after the first dose (2.5 mg) admin- to reverse vecuronium required a median of 50 minutes.58,59
istered for reversal of atracurium-induced neuromuscular Although 0.07 mg/kg neostigmine accelerated recovery from
blockade, which might adversely affect neuromuscular deep blockade by 20–25 minutes, the returned neuromuscular
function.24 It was found that some patients (eight in 60) who function was incomplete and unsatisfactory.5,60
were given 0.04 mg/kg neostigmine at 2–4 hours after a Rather than increasing the doses of neostigmine which are
single dose of vecuronium (0.1 mg/kg) had decreased TOFR limited by the ceiling effects, waiting longer for the improve-
after the administration, and the TOFR of those patients had ment of spontaneous prereversal recovery may be the key to
recovered to $0.9 at the time of reversal, although this effect obtain better effects.32 An anticholinesterase is recommended
was short-lived (only 10–20 minutes).24,52 After administra- to be administered only after the recovery from neuromuscular
tion of neostigmine (0.03 mg/kg) after the TOFR recovered blockade is presented (ie, a TOF count $2), and it was recom-
to unity (.1.0), upper airway collapsibility was increased mended to wait until two twitches were seen before neostig-
and genioglossus muscle activation in response to negative mine administration to reach a TOFR .0.7, and four visible
pharyngeal pressure was impaired in healthy volunteers.53,54 twitches to reach a TOFR of 0.9 within 10–15 minutes.17,61

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Dovepress Recent update on neostigmine for reversal of neuromuscular blockade

Complete recovery (TOFR .0.9) was achieved only if neo- 0.05–0.07 mg/kg neostigmine can be used when TOF count
stigmine was administered when spontaneous recovery was is 2–4 (with fade by tactile or visual means, TOFR ,0.4);
well underway.14 More recently, the recommendation based 0.02–0.03 mg/kg neostigmine can be used when TOF count
on a systematic review indicated that the administration of is 4 (no tactile or visual fade, TOFR =0.4–0.9); and reversal
neostigmine should be delayed until an advanced degree will be unnecessary when TOFR is $0.9.5
of prereversal recovery has occurred (ie, a T1 .25% of
baseline), or the recovery time would be .15 minutes.62 Prevention of adverse effects
Generally, it was indicated that, regarding both the Generally, neostigmine was found to be associated with
reversal time and total recovery time, the optimum time serious adverse events in ,1% of patients.64 Potentially
for neostigmine administration for reversal of atracurium- induced muscle weakness and cholinergic side effects are
induced neuromuscular blockade was when 0, T1 (the first the main concerns.
twitch in TOF) ,8% or when 5, D1 (the first twitch in The neostigmine-induced muscle weakness may mainly
double-burst stimulation) ,15%.56 It is recommended that occur in patients who are administered after full recovery
reversal of profound or deep neuromuscular block not to be and those administered with large doses who are relatively
attempted using neostigmine.5 It is recommended to initi- “overdosed” after nearly full recovery. It has been well
ate neostigmine under neuromuscular monitoring as well. accepted that reversal is unnecessary when TOFR is at
However, a recent retrospective study indicated that neither least 0.9, and an empiric, routine full dose of 0.07 mg/kg
the doses of neostigmine nor the duration to extubation were neostigmine at reversal of light (TOFR of 0.1–0.4) or
affected by the depth of the neuromuscular blockade prior to minimal (TOFR of 0.4–0.9) neuromuscular block is not
reversal, exposing discrepancies between existing guidelines advised.5 The updated results from a study published in
and the actual clinical practice.63 More evidence are needed 2018 showed that 0.04 mg/kg neostigmine administered
if the current concepts of timing of neostigmine administra- for reversal of TOFR of 0.9–1.0 was not associated with
tion are to be updated. clinical evidence of anticholinesterase-induced muscle
weakness.2 Moreover, although 0.03 mg/kg neostigmine
Recommendations of dosing and timing administered after spontaneous recovery to a TOFR of
of neostigmine administration 1.0 induced symptoms of muscle weakness (difficulty
Although the data on dosing and timing of neostigmine admin- swallowing and diplopia) in awake volunteers, there is no
istration seem to vary according to the different NMBDs and evidence to answer the question that whether smaller doses
their doses used, the monitoring of neuromuscular block (#0.03 mg/kg) of neostigmine have an effect on airway
with electrically stimulating indices (eg, TOF and/or TOFR) muscular weakness or residual paralysis if administered at
can provide an objective and standardized measurement (near) full recovery and whether these doses are associated
for evaluation and prediction, and the recommendations of with adverse clinical outcomes when administered empiri-
dosing and timing of neostigmine administration are mainly cally (in the absence of neuromuscular monitoring).5,54
based on the data from neuromuscular monitoring. It was Hence, administration with lower doses under close
recommended that 0.07 mg/kg can be used when TOF is monitoring may help in prevention of the potential-induced
1–2, moderate dosage (0.04–0.05 mg/kg) can be used when weakness in these patients.
TOF is 3–4, and lower dosage (0.02 mg/kg) can be used One of the most severe subsequence from such muscle
for shallow blockade when TOF is 4. Another suggestion weakness is associated with respiratory impairment.
to diminish the incidence of residual curarization by neo- Neostigmine has been found to induce muscle weakness
stigmine was also based on the level of block measured and adversely affect respiratory outcomes, and is associ-
with neuromuscular monitoring: when TOF count is 0–1, ated with an increased occurrence of atelectasis, pulmonary
reversal should be delayed (till TOF count of 2); when edema, desaturations, postoperative pulmonary complication,
TOFR is ,0.4 or count is 2–3, 0.05 mg/kg neostigmine can and longer PACU and hospital stays.26,27,47 However, some
be administered; when TOF count is 4 with fade, 0.04 mg/kg other studies did not demonstrate any clinical evidence of
can be used; when TOFR is 0.4–0.9 or count is 4 without respiratory muscle weakness in postoperative patients.24,30,65,66
fade, 0.02 mg/kg can be used; but when TOFR is $0.9, no Furthermore, it was revealed that postextubation airway
reversal will be necessary.8,20 Newer recommendations are as obstruction is uncommon after neostigmine is used at a TOFR
follows: reversal should be delayed when TOF count is 0–1; of $0.9, and administration of neostigmine with appropriate

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dosage under close monitoring could decrease and even weakness.71 Because of the geriatric physiological changes,
eliminate the risk of postoperative hypoxemic and pulmonary including declined renal function, a decrease in the nicotinic
complications associated with NMBDs.26,47 Moreover, it was acetylcholine receptors concentration at the motor endplate,
even found recently that as compared to those given saline, and the release of acetylcholine from the preterminal axon,
fewer patients administrated with neostigmine after spontane- most NMBDs’ effects are prolonged; meanwhile, the same
ous recovery to a TOFR of 0.9–1.0 experienced moderate or is observed with neostigmine, which may provide some
severe hypoxemia, required stimulation to maintain oxygen- protection against possible recurarization as its prolonged
ation, or needed additional oxygen therapy, although these duration of action may negate the prolonged duration of
differences were not statistically significant, which might be NMBDs action in the elderly.72,73 The time to reach a TOFR
due to the unpowered designation of the study to examine of 0.6 from pancuronium neuromuscular block was longer
the above indices as secondary outcomes.2 The association in the elderly (11±10 vs 5±4 minutes in the young), and the
of neostigmine administration with improvement in several same as the duration of action of neostigmine 0.07 mg/kg to
symptoms of muscle weakness may be resulting from the antagonize metocurine (32 minutes in elderly vs 11 minutes
neostigmine’s reversal effects on preventing residual paresis in young).72,74 The prolonged duration of maximum response
outweigh its potential muscle weakness-inducing effects in to neostigmine may be due to a decrease in extracellular fluid
the cohort of patients who were benefitted with neostigmine volume and initial volume of distribution, which reflect a
administration even after recovery at a TOFR of 0.9–1.0. greater concentration initially available to act at neuromus-
The cardiovascular side effects of neostigmine as an cular junction.13,75 The concomitant increase in the duration
acetylcholinesterase inhibitor are obvious, especially brady- of action of both NMBDs and neostigmine reduces the risk
cardia and related arrhythmia, the prevention of which can be of recurarization.
achieved with the usage of an additional anticholinergic agent A study on comparison between elderly and young
(eg, atropine or glycopyrrolate) prior or concomitantly to patients administered neostigmine (with doses based on
attenuate the parasympathomimetic activity at nonmuscular weight) for the reversal of tubocurarine’s effects after elec-
acetylcholine receptors. Glycopyrrolate (0.5 mg) was found tive limb surgery demonstrated that there was no significant
superior to atropine (1 mg) in protecting against neostigmine difference between the two groups regarding the relationship
(2.5 mg)-induced bradycardia when administered simultane- between TOFR and recovery time, the trends of which were
ously with less tachycardia and cardiac arrhythmias, which is similar.76 Another study comparing healthy elderly patients
due to its more synchronous effects and time course of action with young adults found that the dose–response relationship
matching that of neostigmine better and better regulation on of neostigmine for reversal of doxacurium’s neuromuscular
parasympathetic system, and because it does not cross the blockade was not significantly different, and the average
blood–brain barrier.67 estimated dose of neostigmine required to obtain 70% TOF
Nausea and vomiting are other concerns. Acetylcho- recovery after 10 minutes was 0.0536 mg/kg in young
linesterase inhibitors were initially not recommended as patients compared to 0.0416 mg/kg in elderly (no statisti-
they increase the rate of postoperative nausea and vomiting cal significance).77 Whether there was bias because of the
(PONV), and it was noted that the risk of nausea and emesis relative small size of this study (11 elderly vs 18 young)
was greater with larger doses (.2.5 mg) of neostigmine needs to be taken into consideration.77 Other investigators
than with smaller doses (1.5 mg) or placebo.68 However, reported that there was no significant age-related difference
the supposed emetic properties have not been supported in dose requirements of neostigmine (concerning the plasma
by evidence from meta-analysis.68–70 Omitting neostigmine concentration–response data) in the aged, although the results
simply for PONV is unjustified. ignored the effect of spontaneous recovery and were based on
the continuous background infusion of the NMBDs, which is
Neostigmine for special patients not a routine clinical practice.75 Surprisingly, in another study,
Geriatric patients the authors reported that as compared with that of the young
The elderly are at increased risk for PRNB with an incidence group, the dose–response curve for neostigmine in the elderly
of 57.7% (aged 70–90, being nearly as twice as that of the group was parallel but significantly to the right, which sug-
younger population, aged 18–50, 30%) and associated gested an apparently larger dose requirement in the elderly for
adverse outcomes, including increased PACU and hospital obtaining antagonism of vecuronium blockade.78 Currently,
stay, more hypoxemic events, airway obstruction, and muscle it is more commonly accepted that dosage adjustments are

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Dovepress Recent update on neostigmine for reversal of neuromuscular blockade

not generally needed in geriatric patients, but neuromuscular or doxacurium and the TOFR was recovered in 10 minutes.86
monitoring should be lasted longer than younger adults. In the case of reversal of rocuronium (0.6 mg/kg) blockade,
One focused consideration for the old patients is the even a much smaller dose of neostigmine (0.0071 mg/kg)
cardiac adverse effects of neostigmine. The incidence of new produced the same effect in children aged 2–10 years as 0.0566
postoperative cardiac dysrhythmias was 14% in 21 geriatric mg/kg neostigmine in adults, and there was no advantage with
patients who had received neostigmine (4.40±0.66 mg) neostigmine dosage .0.02 mg/kg administered to antagonize
or pyridostigmine even premixed with glycopyrrolate 90% of rocuronium’s effect in children.87 Recovery from
(0.88±0.15 mg) for reversal of neuromuscular blockade, pancuronium-induced blockade after a large dose of neostig-
but all dysrhythmias occurred in those with preexisting mine (0.071 mg/kg) was more rapid in children than in adults,
cardiovascular diseases.79 Another study on 93 old patients but increasing the dose of neostigmine (0.1 mg/kg, as compared
reported that as compared to pyridostigmine, neostigmine to 0.05 mg/kg) had no significant effect on the total recovery
was associated with a higher incidence of dysrhythmia in all time but increased the variability in children.88,89 When com-
the studied patients, the subcohort of patients with preexisting paring with atropine, glycopyrrolate was found to be as safe
cardiovascular diseases and those who received a halogenated and effective in children in a mixture with neostigmine for
anesthetic (five times greater in this subcohort when com- reversal of neuromuscular blockade, although its advantages
paring neostigmine to pyridostigmine).80 When compared were not as marked as had been observed in adults.90
to that in younger patients, the dosage of anticholinergic It was found that when neostigmine was administered after
agents (glycopyrronium or atropine) given with neostigmine the first twitch reached 10% of control, the rate of recovery
was suggested to be reduced in the patients who were over for vecuronium was dependent on age, which was faster in
65 years old because of the more drastic changes in heart children than in infants and adults.91 It was also found that
rates, and glycopyrronium might be more beneficial.81 the recovery from rocuronium-induced blockade was faster
Whether the adjustment of dosage of neostigmine and/or in children aged 5–10 years than in children aged 1–4 years.92
anticholinergic agents is needed and what is the optimized As compared with children, young children, or infants, the
combination of them in the geriatric patients are still unclear. neonates experienced both the longest spontaneous recov-
Therefore, further studies with high quality and larger sample ery and reversal recovery of neostigmine (0.03 mg/kg) for
size are required to reconfirm the efficacy and safety of rocuronium.93 Further studies on differences between sub-
neostigmine’s optimal administration in the aged. groups of children at different age ranges are required.
The differences in neostigmine’s effects in children as
Pediatric patients compared to that in adults cannot be explained only with a
PRNB was frequently observed in the pediatric patients pharmacokinetic mechanism.38,85 Other contributors to the
(28.1%), but more commonly in cases reversed with neostig- effect of lower dosage of neostigmine in pediatric patients
mine (37.5%), which may be due to the difficulties in assessing include the local differences at the neuromuscular junction in
related indices as compared with adults and the unreliable children (eg, the number and quantity of nicotinic receptors,
onset time and effectiveness without objective neuromuscular amount of acetylcholine reserve, or acetylcholinesterase
monitoring in the children.82 It was held for a long time that enzyme activity), a more rapid circulation time and the
higher doses of neostigmine were needed for appropriate increased cardiac output speeding the delivery of these agents
antagonism of long-acting NMBDs in children.83 In the 1960s, to the neuromuscular junction and the onset of effect, and
large doses of anticholinesterase were used in children than more rapid removal of NMBDs from the neuromuscular
adults to obtain reliable recovery; for example, 0.08 mg/kg junction.38,94,95 Up till now, there have not been enough
neostigmine was administered to antagonize tubocurarine in sound evidence for confirming both the efficacy and safety
neonates.84 However, later studies indicated that the dose–re- of appropriate use of neostigmine to reverse neuromuscular
sponse curve for neostigmine used to antagonize residual block block in pediatric patients, and further studies with more
from tubocurarine was shifted to the left of that of adults, firstly coherent design and measurements are needed.96
questioning the belief that larger doses of anticholinesterase
were needed in children.85 It was found that smaller doses of Acknowledgments
neostigmine were needed in children than in adults (only half This work was supported by the China Scholarship Council
the weight-related dose of adults to produce the same effect) (CSC No 201608505030), the National Natural Science
for antagonism of neuromuscular blockade by pancuronium Foundation of China (Grant No 81201053) and the Science

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Luo et al Dovepress

and Technology Research Program of Chongqing Municipal 18. Maybauer DM, Geldner G, Blobner M, et al. Incidence and duration of
residual paralysis at the end of surgery after multiple administrations
Education Commission (Grant No KJQN201800419). of cisatracurium and rocuronium. Anaesthesia. 2007;62(1):12–17.
19. Pietraszewski P, Gaszyński T. Residual neuromuscular block in elderly
Disclosure patients after surgical procedures under general anaesthesia with rocuro-
nium. Anaesthesiol Intensive Ther. 2013;45(2):77–81.
The authors report no conflicts of interest in this work. 20. Kopman AF, Eikermann M. Antagonism of non-depolarising
neuromuscular block: current practice. Anaesthesia. 2009;64(Suppl 1):
22–30.
References 21. Miller RD, Ward TA. Monitoring and pharmacologic reversal of a
1. Meara JG, Leather AJ, Hagander L, et al. Global Surgery 2030: evidence nondepolarizing neuromuscular blockade should be routine. Anesth
and solutions for achieving health, welfare, and economic development. Analg. 2010;111(1):3–5.
Lancet. 2015;386(9993):569–624. 22. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ.
2. Murphy GS, Szokol JW, Avram MJ, et al. Neostigmine administra- A survey of current management of neuromuscular block in the United
tion after spontaneous recovery to a train-of-four ratio of 0.9 to 1.0: a States and Europe. Anesth Analg. 2010;111(1):110–119.
randomized controlled trial of the effect on neuromuscular and clinical 23. Payne JP, Hughes R, Al Azawi S. Neuromuscular blockade by
recovery. Anesthesiology. 2018;128(1):27–37. neostigmine in anaesthetized man. Br J Anaesth. 1980;52(1):69–76.
3. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the 24. Goldhill DR, Wainwright AP, Stuart CS, Flynn PJ. Neostigmine after
PACU after a single intubating dose of nondepolarizing muscle relaxant spontaneous recovery from neuromuscular blockade. Effect on depth of
with an intermediate duration of action. Anesthesiology. 2003;98(5): blockade monitored with train-of-four and tetanic stimuli. Anaesthesia.
1042–1048. 1989;44(4):293–299.
4. Baillard C, Gehan G, Reboul-Marty J, Larmignat P, Samama CM, 25. Meyer MJ, Bateman BT, Kurth T, Eikermann M. Neostigmine reversal
Cupa M. Residual curarization in the recovery room after vecuronium. doesn’t improve postoperative respiratory safety. BMJ. 2013;346:
Br J Anaesth. 2000;84(3):394–395. f1460.
5. Brull SJ, Kopman AF. Current status of neuromuscular reversal and 26. Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate
monitoring: challenges and opportunities. Anesthesiology. 2017;126(1): acting non-depolarizing neuromuscular blocking agents and risk of
173–190. postoperative respiratory complications: prospective propensity score
6. Arbous MS, Meursing AE, van Kleef JW, et al. Impact of anesthesia matched cohort study. BMJ. 2012;345:e6329.
management characteristics on severe morbidity and mortality. 27. Sasaki N, Meyer MJ, Malviya SA, et al. Effects of neostigmine reversal
Anesthesiology. 2005;102(2):257–268. of nondepolarizing neuromuscular blocking agents on postoperative
7. Bulka CM, Terekhov MA, Martin BJ, Dmochowski RR, Hayes RM, respiratory outcomes: a prospective study. Anesthesiology. 2014;121(5):
Ehrenfeld JM. Nondepolarizing neuromuscular blocking agents, reversal, 959–968.
and risk of postoperative pneumonia. Anesthesiology. 2016;125(4): 28. Fortier LP, McKeen D, Turner K, et al. The RECITE study: a Canadian
647–655. prospective, multicenter study of the incidence and severity of residual
8. Murphy GS, De Boer HD, Eriksson LI, Miller RD. Reversal neuromuscular blockade. Anesth Analg. 2015;121(2):366–372.
(antagonism) of neuromuscular blockade. In: Miller RD, Cohen NH, 29. Bronsert MR, Henderson WG, Monk TG, et al. Intermediate-
Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL, editors. acting nondepolarizing neuromuscular blocking agents and risk of
Miller’s Anesthesia. 8th ed. Philadelphia: Elsevier; 2015:995–1027. postoperative 30-day morbidity and mortality, and long-term survival.
9. Vymazal T, Krecmerova M, Bicek V, Lischke R. Feasibility of full Anesth Analg. 2017;124(5):1476–1483.
and rapid neuromuscular blockade recovery with sugammadex in 30. Choi ES, Oh AY, Seo KS, et al. Optimum dose of neostigmine to reverse
myasthenia gravis patients undergoing surgery – a series of 117 cases. shallow neuromuscular blockade with rocuronium and cisatracurium.
Ther Clin Risk Manag. 2015;11:1593–1596. Anaesthesia. 2016;71(4):443–449.
10. Montague J, Halloran C. Reversing non-depolarising muscle relaxants, 31. Fuchs-Buder T. Neostigmine: timing and dosing in 2016. Anaesth Crit
nausea and residual curarisation. Anaesthesia. 2016;71(4):478. Care Pain Med. 2016;35(4):245–247.
11. Paton F, Paulden M, Chambers D, et al. Sugammadex compared with 32. Fuchs-Buder T, Nemes R, Schmartz D. Residual neuromuscular
neostigmine/glycopyrrolate for routine reversal of neuromuscular block: blockade: management and impact on postoperative pulmonary out-
a systematic review and economic evaluation. Br J Anaesth. 2010; come. Curr Opin Anaesthesiol. 2016;29(6):662–667.
105(5):558–567. 33. Prescott F, Organe G, Rowbotham S. Tubocurarine chloride as an adjunct
12. Cronnelly R, Stanski DR, Miller RD, Sheiner LB, Sohn YJ. Renal to anaesthesia; report on 180 cases. Lancet. 1946;2(6412):80–84.
function and the pharmacokinetics of neostigmine in anesthetized man. 34. Gray TC, Wilson F. The development and use of muscle relaxants in
Anesthesiology. 1979;51(3):222–226. the United Kingdom. Anesthesiology. 1959;20(4):519–529.
13. Morris RB, Cronnelly R, Miller RD, Stanski DR, Fahey MR. 35. Viby-Mogensen J, Jørgensen BC, Ording H. Residual curarization in
Pharmacokinetics of edrophonium and neostigmine when antagonizing the recovery room. Anesthesiology. 1979;50(6):539–541.
d-tubocurarine neuromuscular blockade in man. Anesthesiology. 1981; 36. Fuchs-Buder T, Meistelman C, Alla F, Grandjean A, Wuthrich Y, Donati F.
54(5):399–402. Antagonism of low degrees of atracurium-induced neuromuscular
14. Berkó S, Szűcs KF, Balázs B, et al. Electroporation-delivered transder- blockade: dose–effect relationship for neostigmine. Anesthesiology.
mal neostigmine in rats: equivalent action to intravenous administration. 2010;112(1):34–40.
Drug Des Devel Ther. 2016;10:1695–1701. 37. Harper NJ, Wallace M, Hall IA. Optimum dose of neostigmine at two
15. Kirkegaard H, Heier T, Caldwell JE. Efficacy of tactile-guided reversal levels of atracurium-induced neuromuscular block. Br J Anaesth. 1994;
from cisatracurium-induced neuromuscular block. Anesthesiology. 72(1):82–85.
2002;96(1):45–50. 38. Hunter JM. Is it always necessary to antagonize residual neuromuscular
16. Lien CA. Neostigmine: how much is necessary for patients who receive block? Do children differ from adults? Br J Anaesth. 1996;77(6):
a nondepolarizing neuromuscular blocking agent? Anesthesiology. 707–709.
2010;112(1):16–18. 39. Kaufhold N, Schaller SJ, Stäuble CG, et al. Sugammadex and neostigmine
17. Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. dose-finding study for reversal of residual neuromuscular block at a
Part II: methods to reduce the risk of residual weakness. Anesth Analg. train-of-four ratio of 0.2 (SUNDRO20)†. Br J Anaesth. 2016;116(2):
2010;111(1):129–140. 233–240.

2404 submit your manuscript | www.dovepress.com Therapeutics and Clinical Risk Management 2018:14
Dovepress
Dovepress Recent update on neostigmine for reversal of neuromuscular blockade

40. Magorian TT, Lynam DP, Caldwell JE, Miller RD. Can early admin- 60. Caldwell JE, Robertson EN, Baird WL. Antagonism of profound
istration of neostigmine, in single or repeated doses, alter the course neuromuscular blockade induced by vecuronium or atracurium. Com-
of neuromuscular recovery from a vecuronium-induced neuromuscular parison of neostigmine with edrophonium. Br J Anaesth. 1986;58(11):
blockade? Anesthesiology. 1990;73(3):410–414. 1285–1289.
41. McCourt KC, Mirakhur RK, Kerr CM. Dosage of neostigmine for 61. Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emer-
reversal of rocuronium block from two levels of spontaneous recovery. gence from anesthesia. Anesthesiology. 2010;112(4):1013–1022.
Anaesthesia. 1999;54(7):651–655. 62. Tajaate N, Schreiber JU, Fuchs-Buder T, Jelting Y, Kranke P. Neostigmine-
42. Lederer W, Reiner T, Khuenl-Brady KS. Neostigmine injected 5 minutes based reversal of intermediate acting neuromuscular blocking agents
after low-dose rocuronium accelerates the recovery of neuromuscular to prevent postoperative residual paralysis: A systematic review. Eur J
function. J Clin Anesth. 2010;22(6):420–424. Anaesthesiol. 2018;35(3):184–192.
43. Jones JE, Parker CJ, Hunter JM. Antagonism of blockade produced by 63. Dubovoy T, Housey M, Devine S, Kheterpal S. Observational study on
atracurium or vecuronium with low doses of neostigmine. Br J Anaesth. patterns of neuromuscular blockade reversal. BMC Anesthesiol. 2016;
1988;61(5):560–564. 16(1):103.
44. Schaller SJ, Fink H, Ulm K, Blobner M. Sugammadex and neostigmine 64. Hristovska AM, Duch P, Allingstrup M, Afshari A. Efficacy and safety
dose-finding study for reversal of shallow residual neuromuscular block. of sugammadex versus neostigmine in reversing neuromuscular block-
Anesthesiology. 2010;113(5):1054–1060. ade in adults. Cochrane Database Syst Rev. 2017;8:CD012763.
45. Fuchs-Buder T, Baumann C, De Guis J, Guerci P, Meistelman C. Low- 65. Song IA, Seo KS, Oh AY, et al. Timing of reversal with respect to three
dose neostigmine to antagonise shallow atracurium neuromuscular nerve stimulator end-points from cisatracurium-induced neuromuscular
block during inhalational anaesthesia: a randomised controlled trial. block. Anaesthesia. 2015;70(7):797–802.
Eur J Anaesthesiol. 2013;30(10):594–598. 66. Fox MA, Keens SJ, Utting JE. Neostigmine in the antagonism of the
46. Eikermann M, Houle TT. Antagonism of neuromuscular block: all action of atracurium. Br J Anaesth. 1987;59(4):468–472.
things are poison; only the dose makes a thing not a poison. Br J Anaesth. 67. Ostheimer GW. A comparison of glycopyrrolate and atropine during
2016;116(2):157–159. reversal of nondepolarizing neuromuscular block with neostigmine.
47. McLean DJ, Diaz-Gil D, Farhan HN, Ladha KS, Kurth T, Anesth Analg. 1977;56(2):182–186.
Eikermann M. Dose-dependent association between intermediate- 68. Tramèr MR, Fuchs-Buder T. Omitting antagonism of neuromuscular
acting neuromuscular-blocking agents and postoperative respiratory block: effect on postoperative nausea and vomiting and risk of residual
complications. Anesthesiology. 2015;122(6):1201–1213. paralysis. A systematic review. Br J Anaesth. 1999;82(3):379–386.
48. Eikermann M, Fassbender P, Malhotra A, et al. Unwarranted adminis- 69. Abad-Gurumeta A, Ripollés-Melchor J, Casans-Francés R, et al.
tration of acetylcholinesterase inhibitors can impair genioglossus and A systematic review of sugammadex vs neostigmine for reversal of
diaphragm muscle function. Anesthesiology. 2007;107(4):621–629. neuromuscular blockade. Anaesthesia. 2015;70(12):1441–1452.
49. Kim KS, Cheong MA, Lee HJ, Lee JM. Tactile assessment for the revers- 70. Cheng CR, Sessler DI, Apfel CC. Does neostigmine administration
ibility of rocuronium-induced neuromuscular blockade during propofol produce a clinically important increase in postoperative nausea and
or sevoflurane anesthesia. Anesth Analg. 2004;99(4):1080–1085. vomiting? Anesth Analg. 2005;101(5):1349–1355.
50. Brull SJ, Naguib M. How to catch unicorns (and other fairytales). 71. Murphy GS, Szokol JW, Avram MJ, et al. Residual neuromuscular
Anesthesiology. 2018;128(1):1–3. block in the elderly: incidence and clinical implications. Anesthesiology.
51. Astley BA, Katz RL, Payne JP. Electrical and mechanical responses 2015;123(6):1322–1336.
after neuromuscular blockade with vecuronium, and subsequent antago- 72. Young WL, Matteo RS, Ornstein E. Duration of action of neostig-
nism with neostigmine or edrophonium. Br J Anaesth. 1987;59(8): mine and pyridostigmine in the elderly. Anesth Analg. 1988;67(8):
983–988. 775–778.
52. Caldwell JE. Reversal of residual neuromuscular block with neostigmine 73. Cope TM, Hunter JM. Selecting neuromuscular-blocking drugs for
at one to four hours after a single intubating dose of vecuronium. Anesth elderly patients. Drugs Aging. 2003;20(2):125–140.
Analg. 1995;80(6):1168–1174. 74. Marsh RH, Chmielewski AT, Goat VA. Recovery from pancuronium.
53. Eikermann M, Zaremba S, Malhotra A, Jordan AS, Rosow C, A comparison between old and young patients. Anaesthesia. 1980;
Chamberlin NL. Neostigmine but not sugammadex impairs upper 35(12):1193–1196.
airway dilator muscle activity and breathing. Br J Anaesth. 2008;101(3): 75. Young WL, Backus W, Matteo RS, Ornstein E, Diaz J. Pharmacoki-
344–349. netics and pharmacodynamics of neostigmine in the elderly [abstract].
54. Herbstreit F, Zigrahn D, Ochterbeck C, Peters J, Eikermann M. Anesthesiology. 1984;61(3A):A300.
Neostigmine/glycopyrrolate administered after recovery from neu- 76. Chmielewski AT, Loach AB, Goat VA. Recovery from neuromuscular
romuscular block increases upper airway collapsibility by decreasing blockade. A comparison between old and young patients. Anaesthesia.
genioglossus muscle activity in response to negative pharyngeal pres- 1978;33(6):539–542.
sure. Anesthesiology. 2010;113(6):1280–1288. 77. Koscielniak-Nielsen ZJ, Law-Min JC, Donati F, Bevan DR, Clement P,
55. Caldwell JE. Clinical limitations of acetylcholinesterase antagonists. Wise R. Dose-response relations of doxacurium and its reversal with
J Crit Care. 2009;24(1):21–28. neostigmine in young adults and healthy elderly patients. Anesth Analg.
56. Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, 1992;74(6):845–850.
Pedersen HS, Jensen EW. Optimum time for neostigmine reversal of 78. McCarthy GJ, Cooper R, Stanley JC, Mirakhur RK. Dose-response
atracurium-induced neuromuscular blockade. Can J Anaesth. 1996; relationships for neostigmine antagonism of vecuronium-induced neu-
43(9):932–938. romuscular block in adults and the elderly. Br J Anaesth. 1992;69(3):
57. Engbaek J, Ostergaard D, Skovgaard LT, Viby-Mogensen J. Reversal 281–283.
of intense neuromuscular blockade following infusion of atracurium. 79. Muravchick S, Owens WD, Felts JA. Glycopyrrolate and cardiac dys-
Anesthesiology. 1990;72(5):803–806. rhythmias in geriatric patients after reversal of neuromuscular blockade.
58. Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of profound Can Anaesth Soc J. 1979;26(1):22–25.
rocuronium-induced blockade with sugammadex: a randomized 80. Owens WD, Waldbaum LS, Stephen CR. Cardiac dysrhythmia
comparison with neostigmine. Anesthesiology. 2008;109(5):816–824. following reversal of neuromuscular blocking agents in geriatric
59. Lemmens HJ, El-Orbany MI, Berry J, Morte JB Jr, Martin G. Reversal of patients. Anesth Analg. 1978;57(2):186–190.
profound vecuronium-induced neuromuscular block under sevoflurane 81. Mirakhur RK. Antagonism of neuromuscular block in the elderly.
anesthesia: sugammadex versus neostigmine. BMC Anesthesiol. 2010; A comparison of atropine and glycopyrronium in a mixture with
10(15):15. neostigmine. Anaesthesia. 1985;40(3):254–258.

Therapeutics and Clinical Risk Management 2018:14 submit your manuscript | www.dovepress.com
2405
Dovepress
Luo et al Dovepress

82. Ledowski T, O’Dea B, Meyerkort L, Hegarty M, Von Ungern-Sternberg BS. 90. Black GW, Mirakhur RK, Keilty SR, Love SH. Reversal of non-
Postoperative residual neuromuscular paralysis at an Australian tertiary depolarising neuromuscular block in children: a comparison of atro-
children’s hospital. Anesthesiol Res Pract. 2015;2015:410248. pine and glycopyrrolate in a mixture with neostigmine. Anaesthesia.
83. Cook DR. Muscle relaxants in infants and children. Anesth Analg. 1980;35(9):913–916.
1981;60(5):335–343. 91. Debaene B, Meistelman C, D’Hollander A. Recovery from vecuro-
84. Bush GH, Stead AL. The use of d-tubocurarine in neonatal anaesthesia. nium neuromuscular blockade following neostigmine administra-
Br J Anaesth. 1962;34:721–728. tion in infants, children, and adults during halothane anesthesia.
85. Fisher DM, Cronnelly R, Miller RD, Sharma M. The neuromuscular Anesthesiology. 1989;71(6):840–844.
pharmacology of neostigmine in infants and children. Anesthesiology. 92. Motsch J, Leuwer M, Böttiger BW, Bach A, Schönstedt R, Martin E.
1983;59(3):220–225. Dose-response, time-course of action and recovery of rocuronium
86. Bevan JC, Purday JP, Reimer EJ, Bevan DR. Reversal of doxacurium bromide in children during halothane anaesthesia. Eur J Anaesthesiol
and pancuronium neuromuscular blockade with neostigmine in children. Suppl. 1995;11:73–78.
Can J Anaesth. 1994;41(11):1074–1080. 93. Liu J, Cheng Z. Comparison of neostigmine induced reversal of rocuro-
87. Abdulatif M, Mowafi H, Al-Ghamdi A, El-Sanabary M. Dose-response nium in different age children. Zhonghua Yi Xue Za Zhi. 2016;96(10):
relationships for neostigmine antagonism of rocuronium-induced 807–811.
neuromuscular block in children and adults. Br J Anaesth. 1996;77(6): 94. Fisher DM, Cronnelly R, Sharma M, Miller RD. Clinical pharmacology
710–715. of edrophonium in infants and children. Anesthesiology. 1984;
88. Meakin G, Sweet PT, Bevan JC, Bevan DR. Neostigmine and edro- 61(4):428–433.
phonium as antagonists of pancuronium in infants and children. 95. Cook DR. Paediatric anaesthesia: pharmacological considerations.
Anesthesiology. 1983;59(4):316–321. Drugs. 1976;12(3):212–221.
89. Gwinnutt CL, Walker RW, Meakin G. Antagonism of intense 96. Yang L, Yang D, Li Q, Zuo Y, Lu D. Neostigmine for reversal of neu-
atracurium-induced neuromuscular block in children. Br J Anaesth. romuscular block in paediatric patients. Cochrane Database Syst Rev.
1991;67(1):13–16. 2014;5(5):CD010110.

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