Download Residual Neuromuscular Blockade - American Association of Nurse

AANA Journal Course
6
Update for Nurse Anesthetists
Residual Neuromuscular Blockade
Anna L. Plummer-Roberts, MSN, CRNA
Christina Trost, MSN, CRNA
Shawn Collins, DNP, PhD, CRNA
Ian Hewer, MSN, MA, CRNA
This article provides an update on residual neuromuscular blockade for nurse anesthetists. The neuromuscular junction, pharmacology for producing and
reversing neuromuscular blockade, monitoring sites
and methods, and patient implications relating to
incomplete reversal of neuromuscular blockade are
reviewed. Overall recommendations include using
Objectives
At the completion of this course, the reader should be
able to:
1.Identify the anatomy and physiology of acetylcholine and nicotinic acetylcholine receptors.
2.Describe the method of action of neuromuscular
blocking drugs.
3.Describe the available methods for monitoring recovery from neuromuscular blockade.
4.Discuss the options available to reverse neuromuscular blockade and the optimal timing of reversal.
5.List postoperative implications of residual neuromuscular blockade.
Introduction
Contemporary anesthesia often requires the use of
muscle relaxation for surgical exposure or manipulation
of a patient’s airway. If using muscle relaxation, it is important for anesthesia providers to monitor and reverse
neuromuscular blockade to ensure that the patient has
regained complete neuromuscular function by the end
of surgery. Interestingly, a high percentage of anesthesia
providers both internationally and in the United States
do not monitor neuromuscular recovery and do not use
pharmacologic reversal.1 In an evaluation of factors influencing morbidity and mortality in the first 24 hours
postoperatively, a tenfold increase in death or coma was
associated with the absence of reversal medications.2
multiple settings when employing a peripheral nerve
stimulator for monitoring return of neuromuscular
function and administering pharmacologic reversal
when the train-of-four ratio is below 0.9.
Keywords: Neuromuscular blockade, peripheral nerve
stimulator, residual neuromuscular blockade.
Despite the potential side effects associated with neuromuscular blockade reversal, the potential for serious and
life-threatening respiratory complications in the postanesthesia care unit (PACU) warrants the use of a neuromuscular monitoring device and pharmacologic reversal
as a standard of care to ensure patient safety.
Anatomy and Physiology of Neuromuscular
Junction
To understand the relationship between skeletal muscle
contraction and neuromuscular blockade, some discussion of the physiology is necessary. Acetylcholine (ACh)
is the neurotransmitter responsible for communication
between the peripheral nervous system and the skeletal
muscles. The ACh molecule comprises 1 acetate and 1
choline molecule packaged together in the presynaptic
neuron and then stored as ACh in vesicles called quanta.
When a signal is propagated, hundreds of quanta spill
thousands of ACh molecules out of the presynaptic
neuron and into the synaptic cleft. The ACh molecules
traverse the neuromuscular junction and bind to nicotinic acetylcholine receptors (nAChRs) on the postsynaptic neuron. These nAChRs are found in a functional
area on the postsynaptic motor neuron called the motor
end plate (Figure).
The nAChR is pentameric and composed of 2
α-subunits, and 1 each of β, δ, and ε-subunits. The
α-subunits are the binding sites for ACh. For ACh to cause
AANA Journal Course No. 35: AANA Journal course will consist of 6 successive articles, each with an objective for the reader and
sources for additional reading. This educational activity is being presented with the understanding that any conflict of interest on behalf
of the planners and presenters has been reported by the author(s). Also, there is no mention of off-label use for drugs or products.
Please visit AANALearn.com for information about when the corresponding exam questions for this article will be available.
www.aana.com/aanajournalonline
AANA Journal

February 2016

Vol. 84, No. 1
57
Figure. Neuromuscular Junction
Reproduced with permission from Barash P, Cullen BF. Clinical Anesthesia. 7th ed. Riverwoods, IL: Wolters Kluwer Health; 2013.
Nondepolarizing muscle relaxants
Amino steroids
Benzylisoquinolines
Depolarizing muscle relaxants
(–“curoniums”)
(–“curiums”)
Succinylcholine (ultrashort acting)
Rocuronium (intermediate acting)
Mivacurium (short acting)
Vecuronium (intermediate acting)
Cisatracurium (intermediate acting)
Pancuronium (long acting)
Table 1. Common Pharmacologic Muscle Relaxants
the ligand-gated sodium ion (Na+) channels to open, ACh
must occupy both α subunits. This initiates a depolarization of the motor unit and signals release of calcium ions
(Ca2+) from the sarcoplasmic reticulum, which allows
actin and myosin to interact within the myofibrils of the
muscle, causing a skeletal muscle contraction.
Also present on the motor end plate are thousands of
acetylcholinesterase molecules, the enzyme responsible
for the dissociation of ACh back into its constituents of
acetate and choline. These are inactive constituents and
are taken back into the presynaptic cell and repackaged
into ACh, where they are almost immediately available
for the next muscle contraction.
Neuromuscular Blocking Drugs
Neuromuscular blocking drugs can be classified based on
mechanism of action or duration of action. When classified based on mechanism of action, there are 2 groups: depolarizing muscle relaxants and nondepolarizing muscle
relaxants (NDMRs; Table 1). When classified based on
duration of action, there are 3 groups: short acting (5-20
minutes), intermediate acting (20-55 minutes), and long
acting (60 minutes and longer; see Table 1).3
Muscle relaxants are large molecules with a positively
charged quaternary ammonium group that is attracted
to the negatively charged nAChR. Depolarizing muscle
relaxants, such as succinylcholine, compete with ACh
58
AANA Journal

February 2016

Vol. 84, No. 1
to agonize the nAChR. Similar to ACh, succinylcholine
binds to both α-subunits, causing the motor end plate to
depolarize. The succinylcholine molecule is composed
of 2 linked ACh molecules but differs from ACh in its
resistance to degradation by acetylcholinesterase. During
initial depolarization by succinylcholine, the muscle
fiber undergoes repetitive excitation known as fasciculations, followed by a rest period where no excitation
occurs, which results in paralysis. In the presence of
normal physiology, succinylcholine generally does not
cause postoperative weakness, because of its ultrashort
duration, and is therefore rarely implicated in residual
neuromuscular blockade (RNMB).
There are 2 broad categories of NDMRs: benzylisoquinolines and amino steroids. Unlike the endogenous
ligand (ACh) and the depolarizer (succinylcholine),
NDMRs competitively antagonize the nAChR by binding
to only one α-subunit.4 By antagonizing this receptor, the
motor end plate cannot depolarize and the muscle cannot
contract, resulting in paralysis.
Monitoring Sites of Interest and Nerve
Stimulation
A few types of neuromuscular blockade monitoring
devices warrant discussion, as well as their monitoring
sites, modes of stimulation, and methods for interpretation. Muscle relaxants affect muscles of the body differ-
www.aana.com/aanajournalonline
Mode
Frequency, Hz
Single twitch
Train-of-four
Double burst stimulation
Tetany
Duration
0.1-1
2
50
50, 100, or 200
Pattern
0.2 ms
0.2 ms
4 twitches at 500-ms intervals
0.2 ms2-3 twitches followed by 750-ms pause;
repeat 2-3 twitches
5s
Table 2. Peripheral Nerve Stimulator Settings3,7
ently based on anatomical characteristics (eg, density of
nAChR on motor end plate). The most common sites
for neuromuscular monitoring are the ulnar nerve with
resultant adductor pollicis muscular contraction (adduction of the thumb), temporal branch of the facial nerve
with resultant corrugator supercilii contraction (eyebrow
twitch), zygomatic branch of the facial nerve with resultant orbicularis oculi contraction (eyelid squint), and
posterior tibial nerve with resultant flexor hallucis brevis
contraction (plantar flexion of great toe). Again, because
these muscles are paralyzed and recover from paralysis
at varying times, the site of interest to the anesthesia
provider can change (eg, during intubation vs during
surgical relaxation), or clinical judgment may be necessary to interpret levels of muscle paralysis. For example,
the more central nerves (eg, facial nerve) are paralyzed
faster and recover more quickly than peripheral nerves
(eg, ulnar nerve).5,6 Thus, the corrugator supercilii may
show complete recovery from neuromuscular blockade,
whereas the adductor pollicis shows incomplete recovery.
This requires clinical judgment to evaluate the amount
and timing of pharmacologic reversal.
The peripheral nerve stimulator (PNS) is the most
common neuromuscular stimulating device in clinical
practice and is a qualitative monitoring tool. Electrodes
on the skin attached to the PNS supply current to the
nerve, causing muscle contraction. This is often colloquially termed twitching. Current, supplied in milliamperes,
has a direct relationship with the muscle contraction. The
more current applied to the nerve, the more muscle fibers
innervated by that nerve contraction.7 This is partly what
leads to the qualitative interpretation of the twitch. The
PNS also employs frequency, which is measured in hertz
or cycles per second, and duration in milliseconds.7
The PNS requires the user to select a mode—single
twitch, train-of-four (TOF), double burst stimulation,
or tetany—and then to interpret the response. Response
interpretation can be accomplished by either visualizing
the muscle contraction (if a direct visual can be obtained)
or feeling the muscle contract using a hand lightly placed
on the muscle. This leads to the inherent subjectivity
and variability between providers using the PNS. There
is evidence that tactile assessment may be slightly more
accurate in detecting residual blockade than visual assessment.7,8
There are slight variations between manufacturers, but
the settings can be simplified7 (Table 2). Single twitch
operates at a frequency of 0.1 to 1 Hz with a 0.2-millisecond twitch duration. This mode has limited clinical use.
The TOF employs 4 twitches at 2 Hz of 0.2 milliseconds
in duration. The advantage of this setting is that it allows
for a baseline, for example, comparing twitch number 4
(T4) to twitch number 1 (T1). The twitch “depression”
of T4 compared with T1 is interpreted as the TOF ratio
(TOFR). For example, if T4 is half the twitch strength
of T1, then the TOFR equals 0.5. This twitch depression is what anesthetists have come to know as “fade.”
Clinical data support that when the TOFR exceeds 0.4,
anesthesia providers have trouble assessing the presence of fade, which is a limitation of TOF mode. Double
burst stimulation is essentially 2 or 3 bursts at 50 Hz,
followed by a 750-millisecond pause followed by the
initial burst pattern. Double burst stimulation allows
detection of fade at a TOFR at 0.6 to 0.7, which is most
likely because of the provider’s ability to better assess
differences between 2 stimuli instead of 4.8 Tetany uses
a frequency of 50, 100, or 200 Hz for 5 seconds, which
can also assess fade, although it is intensely painful in a
semi-awake patient. Tetany also produces a posttetanic
facilitation in which a neuromuscular response is elicited
more easily.9,10 This may indicate more recovery than has
actually occurred. Posttetanic count is not a formal mode
but can assess levels of deeper blockade. Posttetanic
count uses tetany followed by TOF at frequency of 1 Hz.
The provider counts the posttetanic TOF twitches (with
no attention to fade). The number of posttetanic count
twitches is inversely related to time until the first regular
(without tetany) TOF twitch returns.
There is some argument among authorities as to the
best test for detecting RNMB. Laboratory work suggests
that mechanomyography (MMG) is the gold standard
for assessing neuromuscular blockade because it quantitatively measures the force of muscle contraction.3,7
However, MMG is not useful in the clinical setting
because of bulky equipment and the need for controlled
variables such as muscle temperature.7 In clinical use, it
is easier for clinicians to assess fade with double burst
stimulation vs TOF, but 100-Hz tetanus over 5 seconds
appears to be the most sensitive test for assessing
RNMB.10-12 Although this is the most sensitive method,
it has shortcomings (eg, painful for an emerging patient)
and thus cannot be used in every situation.
www.aana.com/aanajournalonline
AANA Journal

February 2016

Vol. 84, No. 1
59
Assessment
Devicemodality
Advantages
Small, portable, common in practice
Disadvantages
PNS
Uses current, multiple modes
MMG
Measures force of muscle Gold standard, no user interpretation
contraction
Bulky, difficult to set up,
affected by temperature
AMG
Measures acceleration of muscle response Susceptible to artifact due to
movement
Converts to numerical ratio, inexpensive, easy to use
Requires user interpretation
KMG
Measures bend in sensor Multiple modes
corresponding to muscle contraction
May inaccurately assess
recovery from paralysis
EMG
Measures electrical activity Equipment is less bulky, requires less space
Affected by temperature and
positioning, needs multiple
electrodes, requires calibration
Table 3. Neuromuscular Blockade Monitoring Devices7
Abbreviations: AMG, acceleromyography; EMG, electromyography; KMG, kinemyography; MMG, mechanomyography; PNS, peripheral
nerve stimulator.
There are several quantitative methods of assessing
neuromuscular blockade, including acceleromyography (AMG), kinemyography (KMG), electromyography
(EMG), and MMG (Table 3).7 All these methods use
the ulnar nerve and adductor pollicis muscle (ie, thumb
twitch). These methods are more reliable than qualitative methods. However, all have notable disadvantages.
Ultimately, no current method guarantees complete detection of RNMB.
Acceleromyography measures the acceleration of a
muscle response and converts it to a ratio.7 For example,
rather than the anesthesia provider using the TOF mode
and assessing response, the AMG displays a TOFR based
on the conversion of acceleration. In some models, the
TOFR can exceed 1.0, and in others it does not, leading
to some confusion for interpretation. In clinical practice, the displayed value is susceptible to artifact during
patient movement.
Kinemyography measures the amount of bend in a
sensor when the muscle is stimulated. Sensors on the
thumb and forefinger are responsible for interpreting the
bend. It has single twitch, double burst stimulation, and
TOF modes but may be less useful than MMG in determining recovery.7
Electromyography measures electrical activity in the
nerve being stimulated. It does not require the arm preparation that AMG needs, but its major disadvantage is that
measured electrical activity is influenced by temperature,
which is difficult to keep constant on an extremity even
during short surgeries in a cold operating room.
Mechanomyography converts the force of muscle
contraction to correspond to twitch height, tetany, and
TOFR. Like EMG, muscle temperature affects results,
and thus it is rarely used clinically.
Although PNS and tools for myography, including
AMG, KMG, EMG, and MMG, are useful in the patient
under general anesthesia, other methods are useful in an
awake patient. These methods are flawed by subjectivity
60
AANA Journal

February 2016

Vol. 84, No. 1
Drug
Onset, min
Duration of
action, min
Edrophonium
5-10 Neostigmine
5-15 30-60
45-90
Pyridostigmine
10-20 60-120
Table 4. Common Cholinesterase Inhibitors3
as well. The most potentially useful test is the patient’s
ability to sustain a forceful bite, although the timing of
this test is limited to after extubation. This demonstrates
the strength of the masseter muscle and is associated with
a TOFR of 0.86.10 As will soon be discussed, the gold
standard for adequate recovery is a TOFR greater than
0.9. The traditional 5-second head lift can be successfully performed with a TOFR of 0.5 and thus is not an
appropriate measure of full reversal.8 Analysis of current
evidence reveals that no clinically used test of neuromuscular function can reliably exclude the presence of
residual paralysis less TOFR less than 0.9.8
Reversal of Neuromuscular Blockade
Until recently, the only methods of reversing neuromuscular blockade available in the United States were acetylcholinesterase inhibitors (AChIs): neostigmine, edrophonium, and pyridostigmine (Table 4).3 These agents work
on acetylcholinesterase, the enzyme that breaks down
ACh. By inhibiting this breakdown, the lifespan of ACh
increases as well as the concentration available for action
at the neuromuscular junction.3 The increased quantity
of ACh outcompetes any NDMR remaining in the neuromuscular junction, and the recovery of skeletal muscle
begins.
There is a clinical ceiling effect of AChIs when
100% of acetylcholinesterase has been inhibited, termed
maximal inhibition. At maximal inhibition, additional
doses of AChIs will not improve recovery and could lead
to paradoxical muscle weakness.13 The resultant muscle
www.aana.com/aanajournalonline
weakness may be due to desensitization of ACh receptors
leading to transmission failure, a depolarization block or
open channel block.13 This effect can be seen at clinically
used doses of neostigmine, 0.04 to 0.07 mg/kg.10 The
use of high-dose neostigmine, above 0.06 mg/kg, has
been associated with a threefold increase in the risk of
postoperative atelectasis, longer time to PACU discharge
readiness, and longer postoperative hospital stay.14 The
researchers theorized that these effects could be due to
neostigmine being used in a patient who has complete,
spontaneous recovery from NDMR, resulting in a depolarizing block or an incomplete reversal from a profound
neuromuscular blockade.14
The clinical ceiling effect also limits the ability of
AChIs to reverse profound neuromuscular blockade when
the concentration of NDMR is high at the neuromuscular
junction, such as that corresponding to a TOFR less than
0.2.15 Use of AChIs to achieve adequate recovery to a
TOFR greater than 0.9 can only occur if endogenous recovery at the neuromuscular junction has already begun.
Research has shown that achieving the gold standard
of a TOFR greater than 0.9 within 10 minutes of neostigmine delivery from any degree of paralysis during
a volatile-based anesthetic is not an achievable goal.16
Pharmacologic reversal with neostigmine paired with
glycopyrrolate following muscle relaxation by cisatracurium or rocuronium from a TOF of 2/4 with tactile assessment at the adductor pollicis required an average of 15
minutes to obtain a TOFR of 0.9 or greater; some patients
had residual block (TOFR < 0.9) even at 30 minutes.17
Kim and colleagues18 found that time from reversal to a
TOFR greater than 0.9 took significantly longer periods
of time in sevoflurane-based anesthetic vs propofol-based
anesthetic, demonstrating that volatile anesthetics can
alter the effective onset time of AChIs. They also found
that reversal to a TOFR greater than 0.9 occurred from
2 tactile TOF counts in the propofol-based group, on
average, in 10 minutes. In contrast, from 4 tactile TOF
counts the sevoflurane group took 15 minutes to obtain a
TOFR greater than 0.9 in 95% of patients. From 2 tactile
TOF counts it took the sevoflurane group an average of
22 minutes to achieve a TOFR greater than 0.9. Current
recommendations include waiting until 4 tactile TOF
counts are visible at the adductor pollicis before administering reversal medication; this will allow for adequate
spontaneous recovery and optimization of AChIs action
while allowing approximately 20 minutes after a reversal
agent is given to obtain a TOF greater than 0.9.8,10,15
Aside from nicotinic ACh receptors on skeletal
muscles, ACh can stimulate muscarinic ACh receptors
on sites such as the heart, lungs, and gastrointestinal
tract. Systemic increases in ACh (due to administration
of AChI) can lead to adverse effects such as bradycardia,
arrhythmias, hypotension, bronchoconstriction, hypersalivation, diarrhea, and increased gastric secretions.19
These adverse parasympathetic effects can be prevented
with simultaneous administration of an antimuscarinic
drug (either atropine or glycopyrrolate), which acts by
blocking muscarinic ACh receptors. Because the antimuscarinic drug prevents the ill effects of the AChI, it is
important that the anesthetist selects drugs with similar
onset time and duration of action. Glycopyrrolate is best
paired with neostigmine, whereas atropine is best paired
with edrophonium.
Anesthesia providers cite AChIs’ muscarinic effects
on the gastrointestinal tract (eg, increased motility and
stimulation of gastric secretions and acid) as a cause for
increased incidence of postoperative nausea and vomiting.20 A meta-analysis by Cheng et al21 in 2005 found
that neostigmine paired with an antimuscarinic was not
associated with an increase in the risk of postoperative
vomiting. Insufficient evidence was found to make a
conclusion about postoperative nausea. Interestingly,
they found a significant decrease in postoperative vomiting when atropine was used vs glycopyrrolate. The
authors theorized that the effect of atropine was due
to its ability to cross the blood-brain barrier and exert
central effects.
Plagued with muscarinic side effects, AChIs are no
longer the only method of pharmaceutical reversal of
neuromuscular blockade available. Following the recent
FDA decision sugammadex is now available to providers in the United States, as well as the United Kingdom,
Europe, and Asia.
Sugammadex is the first of a new class of medications
called selective relaxant binding agents, available to reverse
neuromuscular blockade. Its method of action is to selectively encapsulate neuromuscular blocking drugs by
forming tight water-soluble complexes. It encapsulates the
amino steroids (eg, rocuronium, vecuronium, pancuronium), thus rendering them unable to antagonize the nAChR.
These complexes are then excreted intact via urine.3
The 2 primary advantages of sugammadex are the
rapid speed of skeletal muscle recovery (it can reverse
any level of blockade when dosed appropriately within
3 minutes3) and the lack of muscarinic adverse effects.22
The proposed disadvantages of sugammadex are rare
allergic reactions and short-term transient alterations
to prothrombin time.12 Sugammadex has been used
in Europe since 2008, but as noted, has only recently
become available in the United States. It has potential to
revolutionize the reversal of neuromuscular blockade,
but owing to its recent introduction, is beyond the scope
of this article to analyze fully.
It should be noted that numerous factors, including anesthetic management and patient characteristics,
might influence the ability of the anesthetist to achieve a
timely reversal. Some of these factors include increased
levels of inhalation agent, hypothermia, age, and metabolic imbalances.18,19
www.aana.com/aanajournalonline
AANA Journal

February 2016

Vol. 84, No. 1
61
Residual Neuromuscular Blockade
•Definition. To be able to understand the full implications of RNMB, we first must define what RNMB is and
establish how often it occurs in patients undergoing
general anesthesia.
In 1975 RNMB was defined as a TOFR less than 0.7
based on a pulmonary function test in healthy awake
volunteers.23 The study subjects were able to maintain
normal vital capacity, inspiratory force, and expiratory
force with a TOFR of 0.7 or greater.
Donati12 concluded that “the recommended target
of 0.7 for adequate neuromuscular recovery had to be
revised when several groups provided evidence that
swallowing, protection from aspiration, ability to clench
teeth, and genioglossus activity were considerably depressed at a TOFR of 0.7 and that near-normal function was not present until TOFR reached 0.9.” Normal
pulmonary function can be maintained at a TOFR of
0.7 because of the diaphragm’s relative resistance to the
effects of NDMR. This resistance leads to less blockade
at the diaphragm and a quicker recovery than for peripheral muscles such as the adductor pollicis.5 This results
in adequate spontaneous respiration, whereas the TOF
is suppressed and pharyngeal function is still impaired.
A precurarization dose of NDMR, which is a smaller
dose of approximately 10% of the required intubating
dose used to speed the onset of the intubating dose,
has long been known to reduce the TOFR to as low as
0.64.24 A TOFR of 0.85 has been associated with general
discomfort, malaise, ptosis, and blurred vision following
a precurarization dose of vecuronium, pancuronium, or
atracurium.24,25
The current accepted standard of RNMB is a TOFR
less than 0.9. This is based primarily on recovery of laryngeal function. Muscles of the upper airway involved in
swallowing and airway protection are sensitive to small
amounts of residual block.26 After muscle paralysis with
vecuronium and measurement at the adductor pollicis, a
TOFR of 0.8 was associated with significantly decreased
end-inspiratory upper airway volumes, and pharyngeal
function normalized at a TOFR greater than 0.9.27 These
authors concluded that partial paralysis at a TOFR of 0.5
and 0.8 leads to partial upper airway obstruction due to
weakness of the upper airway dilator muscles.28 Another
factor influencing the adjustment upward of the standard
for RNMB is impairment of the hypoxic ventilatory drive
at small amounts of residual paralysis (eg, TOFR = 0.7),
likely due to reduced nerve discharge from carotid body
chemoreceptors caused by NDMR.6,29 Hypoxic ventilatory drive has been shown to recover fully with a TOFR
greater than 0.9.26
Recent evidence supporting the underestimation of
RNMB by anesthesia providers showed a belief that
clinically significant RNMB occurred less than 1% of the
time.1 This is at odds with historical and recent docu-
62
AANA Journal

February 2016

Vol. 84, No. 1
mented rates of RNMB. In the late 1970s when RNMB
was defined as TOFR less than 0.7, RNMB was documented to be occurring in 42% of patients arriving in
the PACU.30 A reanalysis of the same data adjusting for a
TOFR less than 0.9 shows the incidence of RNMB at that
time to be 72%.12 A more recent meta-analysis found the
average rate of RNMB was 41%31 with RNMB defined as
a TOFR less than 0.9.
Debaene et al22 showed a similar rate (ie, 45% of patients) of RNMB at admission to the PACU after a single
intubating dose (2 times the effective dose required to
reduce twitch height by 95%, or ED95) of an intermediateacting NDMR. They also found that 2 hours after administration of the NDMR, 37% patients displayed a TOFR
less than 0.9 with no reversal given. Intermediate-acting
NDMRs have a duration of action of 30 to 60 minutes.3 An
intubating dose of rocuronium has been shown to have a
duration of action of 30 to 90 minutes.3 Yet 2 hours after
an intubating dose of intermediate-acting NDMR, 37% of
patients still had some degree of RNMB. Textbook-cited
drug duration times do not guarantee full return of neuromuscular function, and clinically significant RNMB can
occur after the proposed duration.
There is controversy regarding the role neuromuscular monitoring devices play in the prevention of RNMB.
Some of this controversy is due to the lack of clarity in
the available research. A meta-analysis of neuromuscular monitoring and RNMB concluded that the use of
intraoperative neuromuscular monitoring devices is not
associated with a decrease in the incidence of residual paralysis.31 However, the authors suspect the findings may
be due to poor quality and design of studies included in
the analysis. The findings emphasize that merely monitoring neuromuscular blockade does ensure adequate
recovery; in fact, at a TOFR above 0.9, patients can still
have residual paralysis, and a clinically appropriate dose
of reversal should still be warranted even if recovery
appears adequate.
In a more recent study, researchers found less incidence of RNMB with quantitative monitoring (AMG)
compared with qualitative monitoring (PNS).32 At arrival
to the PACU, 14.5% of patients monitored with AMG
exhibited RNMB, whereas 50% of patients monitored
with PNS exhibited RNMB. The patients monitored with
AMG had fewer symptoms of residual paralysis than did
patients monitored with PNS. The use of qualitative TOF
assessment did not decrease the risk of postoperative respiratory complications and reintubation.33
Aside from impaired respiratory ability, which is of
utmost concern for the anesthetist, RNMB manifests in numerous other signs of muscle weakness. A study of healthy
volunteers receiving an infusion of mivacurium to obtain a
TOFR of 0.7 via PNS at the adductor pollicis reported diplopia, difficulty with visual tracking, difficulty swallowing,
flat facial expression, and facial muscle weakness.34
www.aana.com/aanajournalonline
Murphy and colleagues32 found that symptoms of
muscle weakness are predictive of the presence or
absence of a TOFR less than 0.9. Patients’ subjective feelings of muscle weakness were considered symptoms of
RNMB. They included the level of perceived difficulty in
completing 11 clinical signs of muscle weakness (normal
vs impaired), blurry vision, double vision, facial weakness, facial numbness, and general weakness. The most
common signs and symptoms at admission to the PACU
were generalized weakness, patient-reported difficulty
completing 5-second eye opening, difficulty visually
tracking and speaking, and blurry vision. These findings
are indicative of ocular and pharyngeal muscle sensitivity to RNMB. The most commonly reported symptom
in patients with a TOFR greater than 0.9 was difficulty
visually tracking.35 All patients with a TOFR less than 0.9
had at least 1 symptom at admission to the PACU, with
a median of 7 symptoms. Of the 80% of patients exceeding a TOFR of 0.9, all had at least 1 symptom of RNMB
at admission to PACU, with a median of 2 symptoms.35
Interestingly, even after 1 hour in the PACU, 83% of
patients who had a TOFR less than 0.9 at admission retained symptoms of residual paralysis.
In terms of clinical tests of RNMB (eg, 5-second head
lift), it appears that these measurements correlate with
a TOFR of 0.6 to 0.7 and are therefore poor indicators
of TOFR less than 0.9.32 These clinical tests include
5-second head lift, 5-second hand grip, 5-second eye
opening, 5-second tongue protrusion, tongue depressor
test, ability to smile, ability to swallow, ability to speak,
ability to cough, ability to visually track objects, and
ability to breathe easily. The median number of failed
clinical tests observed in all patients, despite their level
of RNMB, was zero.32
•Postoperative Implications of Residual Neuromuscular
Blockade. Numerous large retrospective studies have
noted an association between the use of NDMR, residual
paralysis, and adverse postoperative outcomes.2,26,33,36
Overall, critical respiratory events occur between 0.8%
and 6.9% after extubation in the PACU.33,36 Critical
respiratory events include upper airway obstruction,
hypoxia, hypoxemia, signs of respiratory failure, inability
to breathe deeply when instructed, evidence or suspicion
of postextubation aspiration, and reintubation. The most
frequently seen critical respiratory events in the first 15
minutes in the PACU are severe hypoxemia (pulse-oximeter saturation < 90%), upper airway obstruction, and
mild hypoxia (oxygen saturation, 90%-93%).36 Multiple
critical respiratory events may occur concomitantly in
the same patient.36 In a study by Murphy et al36 90.5% of
patients who experienced a critical respiratory event had
a TOFR less than 0.9 as measured by AMG.
In patients needing reintubation, researchers found a
reintubation rate of 0.8%33 occurring an average of 2.5
days postoperatively. Grosse-Sundrup et al33 concluded
that the use of intermediate-acting NDMR is associated with increased risk of postoperative reintubation,
requiring admission to the intensive care unit. When
intermediate-acting NDMRs are used for surgeries less
than 120 minutes, the risk of reintubation is even higher.
Interestingly, the researchers found that the use of
neostigmine increased the risk of severe postoperative
respiratory failure, most likely because of inappropriate
use of neostigmine leading to paradoxical neuromuscular
blockade. In an evaluation of factors influencing morbidity and mortality in the first 24 hours postoperatively, a
tenfold increase in death or coma was associated with the
absence of reversal medications.2
The time spent by patients with RNMB in the PACU
can be significantly longer than patients who had adequate reversal of neuromuscular blockade. Butterly et
al37 documented that patient discharge time from the
PACU is, on average, 75 minutes longer for patients with
RNMB. These researchers also found that the independent risk factors associated with a longer PACU stay were
age and RNMB.37
•Patient Satisfaction. Healthcare reform is increasingly linking reimbursement for services with patient satisfaction. Although it has not yet been determined how
anesthesia reimbursement will be influenced, patient satisfaction is always an area for concern. Patients’ perception of the quality of their recovery has been found to be
more positive with AMG neuromuscular monitoring vs
PNS. Patients ranked overall quality of recovery based on
a 0 to 100 visual analog scale.32 The quality was ranked
higher in the AMG group, who also had significantly less
RNMB.32 In global quality of recovery, measured on the
www.aana.com/aanajournalonline
AANA Journal
•The longer the duration of action of NDMR used, the greater
the frequency of residual paralysis.
•If rocuronium or vecuronium was used, sugammadex may
be used for moderate or deep muscle relaxation in adult
(including elderly) patients and reversal of rocuroniuminduced moderate muscle relaxation in pediatric patients
(aged 2-17 years).
•If not using sugammadex, before paralytic reversal, allow
some degree of spontaneous recovery, ideally a TOFR > 0.9.
•Merely monitoring neuromuscular blockade does ensure
adequate recovery; in fact, at a TOFR > 0.9, patients can still
have residual paralysis, and a clinically appropriate dose of
reversal should still be warranted even if recovery “seems”
adequate.
•Patients monitored with AMG have fewer symptoms of
residual paralysis than do patients monitored with PNS.
•If using a PNS, gather information from multiple modes. A
reduced reversal dose seems clinically prudent even if the
TOFR appears > 0.9.
Table 5. Recommendations
Abbreviations: AMG, acceleromyography; NDMR, nondepolarizing
muscle relaxants; PNS, peripheral nerve stimulator; TOFR, train-offour ratio.

February 2016

Vol. 84, No. 1
63
quality of recovery (QoR)-9 scoring system,38 the groups
differed in one category, with the AMG group having a
higher score in general well-being.
Conclusion
Residual neuromuscular blockade is a complex and
dynamic issue. Because of shortcomings associated with
neuromuscular monitoring tools and differing recovery
rates based on physiology, interpreting patient recovery
can be difficult. Current literature outlines some of the
issues that contribute to RNMB and the complications
that are associated with it. Understanding the complexity of these issues can lead to increased patient safety.
Based on current literature, our recommendations are
presented in Table 5.
REFERENCES
1. Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A
survey of current management of neuromuscular block in the United
States and Europe. Anesth Analg. 2010;111(1):110-119.
2. Arbous MS, Meursing AEE, van Kleef JW, et al. Impact of anesthesia
management characteristics on severe morbidity and mortality. Anesthesiology. 2005;102(2):257-268.
3. Nagelhout J. Neuromuscular blocking agents reversal agents, and
their monitoring. In: Nagelhout J, Plaus K, eds. Nurse Anesthesia. 5th
ed. St Louis, MO: Saunders; 2014:158-185.
4. Naguib MLC, Meistelman C. Pharmacology of neuromuscular blocking drugs. In: Miller RD, ed. Miller’s Anesthesia. 8th ed. Philadelphia,
PA: Churchill Livingstone/Elsevier; 2015:958-994.
5. Donati F, Meistelman C, Plaud B. Vecuronium neuromuscular blockade at the diaphragm, orbicularis oculi and adductor pollicis muscles.
Can J Anaesth. 1991;37(4 pt 2):S13-S13.
16. Kirkegaard H, Heier T, Caldwell JE. Efficacy of tactile-guided reversal
from cisatracurium-induced neuromuscular block. Anesthesiology.
2002;96(1):45-50.
17. Kopman AF, Kopman DJ, Ng J, Zank LM. Antagonism of profound
cisatracurium and rocuronium block: the role of objective assessment
of neuromuscular function. J Clin Anesth. 2005;17(1):30-35.
18. Kim KS, Cheong MA, Lee HJ, Lee JM. Tactile assessment for the reversibility of rocuronium-induced neuromuscular blockade during propofol or sevoflurane anesthesia. Anesth Analg. 2004;99(4):1080-1085.
19.Nagelhout JJ, Welliver MD. Reversal of neuromuscular blocking
agents: current practice. AANA J. 2013(suppl):8-11.
20. Tramèr MR, Fuchs-Buder T. Omitting antagonism of neuromuscular
block: effect on postoperative nausea and vomiting and risk of residual paralysis: a systematic review. Br J Anaesth. 1999;82(3):379-386.
21. Cheng C-R, Sessler DI, Apfel CC. Does neostigmine administration
produce a clinically important increase in postoperative nausea and
vomiting? Anesth Analg. 2005;101(5):1349-1355.
22. Debaene B, Plaud B, Dilly MP, Donati F. Residual paralysis in the
PACU after a single intubating dose of nondepolarizing muscle
relaxant with an intermediate duration of action. Anesthesiology.
2003;98(5):1042-1048.
23. Ali HH, Wilson RS, Savarese JJ, Kitz RJ. The effect of tubocurarine
on indirectly elicited train-of-four muscle response and respiratory
measurements in humans. Br J Anaesth. 1975;47(5):570-574.
24. Engbaek J, Howardy-Hansen P, Ôrding H, Viby-Mogensen J. Precurarization with vecuronium and pancuronium in awake healthy volunteers: the influence on neuromuscular transmission and pulmonary
function. Acta Anaesthesiol Scand. 1985;29(1):117-120.
25. Howardy-Hansen P, Moller J, Hansen B. Pretreatment with atracurium: the influence on neuromuscular transmission and pulmonary
function. Acta Anaesthesiol Scand. 1987;31(7):642-644.
26.Murphy GS, Brull SJ. Residual neuromuscular block: lessons
unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg.
2010;111(1):120-128.
6. Murphy GS BH, Eriksson LI, Miller RD. Reversal (antagonism) of
neuromuscular blockade. In: Miller RD, ed. Miller’s Anesthesia. 8th
ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2015:995-1027.
27. Eriksson LI, Sundman E, Olsson R, et al. Functional assessment of the
pharynx at rest and during swallowing in partially paralyzed humans:
simultaneous videomanometry and mechanomyography of awake
human volunteers. Anesthesiology. 1997;87(5):1035-1043.
7. Dorsch JA, Dorsch SE. Understanding Anesthesia Equipment. 5th ed.
Philadelphia PA: Wolters Kluwer Health/Lippincott Williams &
Wilkins; 2008:805-827.
28. Eikermann M, Vogt FM, Herbstreit F, et al. The predisposition to
inspiratory upper airway collapse during partial neuromuscular
blockade. Am J Respir Crit Care Med. 2007;175(1):9-15.
8.Brull SJ, Murphy GS. Residual neuromuscular block: lessons
unlearned. Part II: methods to reduce the risk of residual weakness.
Anesth Analg. 2010;111(1):129-140.
29. Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced
partial neuromuscular block on hypoxic ventilatory response. Anesthesiology. 1993;78(4):693-699.
9. Brull SJ, Connelly NR, O’Connor TZ, Silverman DG. Effect of tetanus on subsequent neuromuscular monitoring in patients receiving
vecuronium. Anesthesiology. 1991;74(1):64-70.
30. Viby-Mogensen J, Jørgensen BC, Ording H. Residual curarization in
the recovery room. Anesthesiology. 1979;50(6):539-541.
10. Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology. 2010;112(4):1013-1022.
31. Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and
postoperative residual curarisation: a meta-analysis. Br J Anaesth.
2007;98(3):302-316.
11. Baurain MJ, Hennart DA, Godschalx A, et al. Visual evaluation of
residual curarization in anesthetized patients using one hundredhertz, five-second tetanic stimulation at the adductor pollicis muscle.
Anesth Analg. 1998;87(1):185-189.
32. Murphy GS, Szokol JW, Avram MJ, et al. Intraoperative acceleromyography monitoring reduces symptoms of muscle weakness and
improves quality of recovery in the early postoperative period. Anesthesiology. 2011;115(5):946-954.
12. Donati F. Residual paralysis: a real problem or did we invent a new
disease? Can J Anaesth. 2013;60(7):714-729.
33. Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate
acting non-depolarizing neuromuscular blocking agents and risk of
postoperative respiratory complications: prospective propensity score
matched cohort study. Br J Anaesth. 2012;345:e6329.
13. Eikermann M, Fassbender P, Malhotra A, et al. Unwarranted administration of acetylcholinesterase inhibitors can impair genioglossus and
diaphragm muscle function. Anesthesiology. 2007;107(4):621-629.
14. Sasaki N, Meyer MJ, Malviya SA, et al. Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes: a prospective study. Anesthesiology.
2014;121(5):959-968.
15. Brull SJ, Kopman AF, Naguib M. Management principles to reduce
the risk of residual neuromuscular blockade. Curr Anesthesiol Rep.
2013;3:13-138.
64
AANA Journal

February 2016

Vol. 84, No. 1
34. Kopman AF, Yee PS, Neuman GG. Relationship of the train-of-four
fade ratio to clinical signs and symptoms of residual paralysis in
awake volunteers. Anesthesiology. 1997;86(4):765-771.
35. Murphy GS, Szokol JW, Avram MJ, et al. Postoperative residual neuromuscular blockade is associated with impaired clinical recovery.
Anesth Analg. 2013;117(1):133-141.
36. Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender
JS. Residual neuromuscular blockade and critical respiratory events in
www.aana.com/aanajournalonline
the postanesthesia care unit. Anesth Analg. 2008;107(1):130-137.
37.Butterly A, Bittner EA, George E, Sandberg WS, Eikermann M,
Schmidt U. Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge.
Br J Anaesth. 2010;105(3):304-309.
38. Myles PS, Hunt JO, Nightingale CE, et al. Development and psychometric testing of a quality of recovery score after general anesthesia
and surgery in adults. Anesth Analg. 1999;88(1):83-90.
39. Hibbs RE, Zambon AC. Agents acting at the neuromuscular junction
and autonomic ganglia. In: Brunton LL (ed). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics. 12th ed. New York, NY:
McGraw-Hill; 2011:254-276.
thetist in High Point, North Carolina, and was a student at Western Carolina
University, Asheville, North Carolina, at the time this article was written.
Christina Trost, MSN, CRNA, is a Certified Registered Nurse Anesthetist in Royal Oak, Michigan, and was a student at Western Carolina
University, Asheville, North Carolina, at the time this article was written.
Shawn Collins, DNP, PhD, CRNA, is the program director of Western
Carolina University Nurse Anesthesia Program, Asheville, North Carolina.
Ian Hewer, MSN, MA, CRNA, is the assistant program director of Western
Carolina University Nurse Anesthesia Program, Asheville, North Carolina.
DISCLOSURES
Anna L. Plummer-Roberts, MSN, CRNA, is a Certified Registered Nurse Anes-
The authors have declared no financial relationships with any commercial
interest related to the content of this activity. The authors did not discuss
off-label use within the article.
www.aana.com/aanajournalonline
AANA Journal
AUTHORS

February 2016

Vol. 84, No. 1
65