*Current Status of Neuromuscular Reversal and Monitoring*

[4/5, 10:15 PM] -: Neuromuscular monitoring devices were introduced into clinical practice in the
1970s.
[4/5, 10:16 PM] -: General Principles
The key to understanding the limitations of acetylcholinesterase antagonists (or
acetylcholinesterase inhibitors, also named anticholinesterases) is to remember that
nondepolarizing block is competitive in nature. Molecules of acetylcholine compete with NMBA
molecules for access to the postsynaptic receptor at the neuromuscular junction. When an
acetylcholinesterase inhibitor is administered, acetylcholine breakdown is slowed, the
acetylcholine concentration at the synaptic cleft increases, and the balance between the
transmitter and blocking agent concentrations shifts in favor of acetylcholine-mediated normal
function (resulting in reversal of block). However, once acetylcholinesterase activity is fully
inhibited, the administration of any additional acetylcholinesterase inhibitor can have no further
effect. Thus, there is a limit to the maximal concentration of acetylcholine that can exist at the
receptor. However, there is no such limit to the concentration of NMBA molecules that can be
present at the neuromuscular junction if the clinician administers very large doses of NMBA.
[4/5, 10:18 PM] -: There is no current agreement on how to define profound (intense) versus
deep versus moderate versus light (shallow) neuromuscular block. Suggested Definitions of
Depth of Neuromuscular Block Based on Subjective and Measured (Objective) Criteria.

[4/5, 10:20 PM] -: During a nondepolarizing block, the high frequency of tetanic stimulation will
induce a transient increase in the amount of acetylcholine released from the presynaptic nerve
ending, such that the intensity of subsequent muscle contractions will be increased (potentiated)
briefly (period of post-tetanic potentiation, which may last 2 to 5 min; fig). The neuromuscular
response to stimulation during posttetanic potentiation can be used to gauge the depth of block
when TOF stimulation otherwise evokes no responses (i.e., when the TOF count [TOFC] = 0).
The number of posttetanic responses is inversely proportional to the depth of block: fewer
posttetanic contractions denote a deeper block. When the posttetanic count (PTC) is 6 to 8,
recovery to TOFC = 1 is likely imminent from an intermediate-duration blocking agent; when the
PTC is 0, the depth of block is profound, and no additional NMBA should be administered.
[4/5, 10:24 PM] -: Recovery times are also dependent on the class of nondepolarizing agent
being antagonized (short-, intermediate-, or long-acting) and on the cumulative dose of the drug
that has been administered before attempted pharmacologic reversal. The peak effects of
edrophonium, neostigmine, and pyridostigmine occur in 1 to 2, 7 to 11, and 12 to 16 min,
respectively. Thus, any observed recovery after these intervals is a result of elimination or
redistribution of the NMBA from the plasma.
[4/5, 10:26 PM] -: Achieving prompt and reliable recovery of neuromuscular function by
acetylcholinesterase inhibitor administration when T1 is less than or equal to 10% of control
(corresponding to TOFC less than or equal to 1) is simply not a realistic goal. Attempted
reversal at a TOFC = 1 is also an especially poor idea when objective (quantitative) monitoring
of neuromuscular function is not employed.
[4/5, 10:27 PM] -: At the shallower end of moderate block (TOFC = 3; table), the median
recovery time to a TOF ratio of 0.90 after 0.07 mg/kg neostigmine administration was reported
as 17 (range, 8 to 46) min during nitrous oxide/propofol anesthesia.
[4/5, 10:29 PM] -: To achieve rapid (within 10 min) reversal to a TOF ratio of 0.7 in more than
87% of patients, three or four tactile responses should be present at the time of neostigmine
administration.
[4/5, 10:30 PM] -: Once the TOFC reaches 4 with minimal or absent TOF fade, the reliability
(and speed of reversal) of acetylcholinesterase inhibitors increases markedly.
[4/5, 10:34 PM] -: Neostigmine-induced Neuromuscular Weakness
In 1980, it was reported that when 2.5 mg neostigmine was given to subjects who previously
had not been given a nondepolarizing relaxant, there was a substantial reduction in the peak
tetanic contraction; severe tetanic fade, which persisted for about 20 min, was observed.
[4/5, 10:35 PM] -: The question whether smaller doses of neostigmine (e.g., 0.01 to 0.03 mg/kg)
have any effects of airway musculature weakness or residual paralysis if administered to fully
(or near fully) recovered adult or pediatric patients remains unanswered. These data suggest
that empiric, routine full-dose (neostigmine 0.07 mg/kg) reversal of light or minimal
neuromuscular block is not advised, and they underscore the need for objective neuromuscular
monitoring. At this shallow end of the reversal spectrum, however, there does not appear to be
any evidence to suggest that doses of neostigmine of 0.03 mg/kg or less are associated with
adverse clinical outcomes when administered empirically (i.e., in the absence of neuromuscular
monitoring). However, there is evidence that in the absence of routine reversal, the incidence of
postoperative residual neuromuscular block and associated complications is markedly
increased.
[4/5, 10:35 PM] -: *Recommendations for Pharmacologic Antagonism of Nondepolarizing
Blockade According to the Depth of Block*
[4/5, 10:38 PM] -: *Qualitative neuromuscular devices* (or more accurately named, PNSs) are
utilized in most clinical practices. These battery-powered devices provide an electrical stimulus
to a peripheral nerve (most commonly the ulnar nerve), and the response of the stimulated
muscle (usually the thumb) is evaluated subjectively by visual or tactile means. The presence or
absence of muscle weakness is determined by evaluating fade (decreasing muscle
contractions) with repetitive nerve stimulation. Clinicians use several different patterns of nerve
stimulation in order to evaluate fade. The most common pattern of nerve stimulation is TOF.
[4/5, 10:39 PM] -: OF stimulation consists of four stimuli at 2-Hz frequency. The force of
contraction of the fourth muscle twitch is subjectively compared to the contraction of the first
twitch, and fade is considered absent when both muscle contractions (twitches) appear equal
(no block; fig.). When the fourth twitch in the TOF sequence starts decreasing in amplitude, the
TOF ratio becomes less than 1.0 and TOF fade ensues (partial block; fig.).
[4/5, 10:41 PM] -: The effectiveness of qualitative neuromuscular monitoring in decreasing the
incidence of residual blockade remains controversial since this type of monitoring is ineffective
in detecting residual blockade when TOF ratios are more than 0.40
[4/5, 10:44 PM] -: While other stimulation patterns such as double-burst stimulation (DBS; fig.)
were introduced into clinical care to facilitate the subjective assessment of fade, such attempts
have been minimally successful: the threshold (lowest TOF ratio) for detection of fade using
subjective evaluation of TOF is approximately 0.40, while the TOF threshold for detecting DBS
fade is 0.60. Thus, even when there is no tactile detection of fade to either TOF or DBS
stimulation, there is almost a 50% risk that the actual measured ratio is below 0.70. Clearly, the
proportion of clinicians who will miss the presence of residual block will be even higher at the
recovery TOF threshold of 0.9.
[4/5, 10:46 PM] -: A double burst stimulus (DBS) consists of two brief, 50-Hz tetanic bursts
delivered 0.75 s apart. Each burst consists of three stimuli (DBS3,3) that result in two sustained
muscle contractions. The DBS ratio (D2/D1) approximates the train-of-four (TOF) ratio. When
quantitative monitoring is not available, the advantage of DBS over TOF is that subjectively
determined fade is more easily perceived than the fade induced by TOF stimulation. However,
once the TOF ratio exceeds 0.60, fade to DBS generally cannot be detected subjectively.
[4/5, 10:47 PM] -: In the unblocked state, the peak height of an evoked mechanical response to
5-s tetanic stimulation (TET) stimulation is generally 7 to 10 times that of a single stimulus, and
the muscle contraction in response to a 5-s, 50-Hz tetanus can be well sustained. During a
partial nondepolarizing neuromuscular block, tetanic tension exhibits fade (decreases in
strength over time). The tetanic stimulation is followed by a 2- to 5-min period of posttetanic
facilitation.
[4/5, 10:48 PM] -: Realizing the limitations of subjective evaluation of TOF fade and readiness
for tracheal extubation, some clinicians rely on the use of PNS to determine the depth of block
and degree of recovery before administering pharmacologic reversal by counting the number of
responses to TOF stimulation (TOFC; fig.).
[4/5, 10:49 PM] -: During moderate block, once the train-of-four (TOF) ratio becomes 0 (i.e., T4
disappears), the depth of block may be assessed by counting the number of responses to TOF
stimulation. The depth of neuromuscular block is proportional to the TOF count (TOFC): the
lower the count, the deeper the block.
[4/5, 10:51 PM] -: *Which nerve to stimulate and when?*
[4/5, 10:54 PM] -: It must be remembered that onset and offset of block is faster in central
muscles with a good blood supply, for example, diaphragm and larynx. Conversely peripheral
muscles, with a relatively poor blood supply, will have a slower onset of block and a longer
recovery time, for example, adductor pollicis. The muscles of the upper airway and pharynx
behave as central muscles at onset; however, they are sensitive to neuromuscular blocking
drugs and recovery is slow, mirroring the peripheral muscles.
[4/5, 10:54 PM] -: *Induction of anaesthesia*

During induction of anaesthesia and tracheal intubation, the muscles of the larynx and jaw must
be paralysed as well as the diaphragm. The orbicularis oculi is probably the ideal muscle to
monitor at this time as it is more similar to a central muscle: onset of block will be similar to the
laryngeal muscles and diaphragm. Single twitch or TOF stimulation is the most valuable
stimulation pattern at induction. Single twitch stimulation will allow the maximal stimulation level
to be obtained. Disappearance of the TOF will correspond to optimal intubating conditions.
[4/5, 10:54 PM] -: *Maintenance of anaesthesia*

As the diaphragm is relatively resistant to neuromuscular block, a more sensitive peripheral

Before administering a neuromuscular antagonist, the TOF count should be at least 3. At this
time, monitoring a peripheral muscle such as adductor pollicis is the best option. The respiratory
muscles are likely to have recovered to a greater degree, and monitoring a peripheral muscle
provides a larger margin of safety.

[4/5, 10:57 PM] -: Ref: Conor D McGrath, Jennifer M Hunter, Monitoring of neuromuscular block,
Continuing Education in Anaesthesia Critical Care & Pain, Volume 6, Issue 1, February 2006,
Pages 7–12,
[4/5, 10:57 PM] -: Ref: Sorin J. Brull, Aaron F. Kopman; Current Status of Neuromuscular
Reversal and Monitoring: Challenges and Opportunities. Anesthesiology 2017;126(1):173-190.