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Antagonism of nondepolarizing blockade is time dependent. Reversal occurs at a rate that depends primarily on five factors: (1) the depth of block at the time of administration of the antagonist, (2) the antagonist administered,
As was shown with the long-acting neuromuscular blocker pancuronium, more time is required to antagonize profound levels of block than lesser levels of block.[254] [581] [582] Antagonism of pancuronium blockade with 2.5 mg (about 35 µg/kg) of neostigmine shows that the relationship of reversal time to depth of blockade is hyperbolic, with a "knee" in the curve occurring at 80% to 90% twitch inhibition ( Fig. 13-28 ). Lesser degrees of block are associated with more rapid recovery of neuromuscular function. Recovery of single-twitch height from deep levels of neuromuscular blockade requires, as demonstrated in these older studies, 15 to 30 minutes. Recovery of the TOF ratio occurs more slowly than that of a single twitch. Therefore, even more time will be required for recovery to a TOF ratio of more than 0.7 when blockade by long-acting drugs is being antagonized.
Interestingly, a study by Bevan and coworkers[583] demonstrated that antagonism of 1.5 × ED95 doses of vecuronium- or rocuronium-induced block occurred at the same rate regardless of the timing of administration of the 70 µg/kg neostigmine. Neostigmine shortened recovery, whether administered at 1%, 10%, or 25% spontaneous recovery, by approximately 40%. As shown in Figure 13-29 , the time from administration of the neuromuscular blocker to TOF ratios of 0.7 and 0.9 was not decreased, though, because the extent of spontaneous recovery at the time of neostigmine administration increased. Recovery to TOF ratios of 0.7 and 0.9 required, on average, 25 and 30 minutes, respectively. Recommendations regarding the timing of administration of anticholinesterase remain unclear. However, because the time from administration of the anticholinesterase to full recovery is shortened by waiting for a greater degree of spontaneous recovery before administering the anticholinesterase, it would seem prudent to not administer the anticholinesterase at the earliest
Figure 13-28
Correlation between twitch height when a bolus of neostigmine
(2.5 mg) was given intravenously and the time that it took for twitch height to return
to its control height. (Redrawn from Katz RL: Clinical neuromuscular pharmacology
of pancuronium. Anesthesiology 34:550–556, 1971.)
Figure 13-29
Recovery times (mean ± SD) after administration
of a single dose of 0.45 mg/kg (1.5 × ED95
)
rocuronium. In one group (Spont), spontaneous recovery is allowed. In the remaining
groups, 70 µg/kg neostigmine is administered 5 minutes after rocuronium or
at 1%, 10%, and 25% recovery of the first twitch (T1) from its control value. *P
< 0.01 versus spontaneous recovery. Note that times to attain a train-of-four
ratio of 0.9 are significantly shorter when neostigmine is administered at T1 = 10%
or 25% of control tension. (Figure constructed based on data redrawn from
Bevan JC, Collins L, Fowler C, et al: Early and late reversal of rocuronium and
vecuronium with neostigmine in adults and children. Anesth Analg 89:333–339,
1999.)
The maximum antagonistic effect of neostigmine occurs in 10 minutes or less.[585] [586] If adequate recovery does not occur within this time, subsequent recovery is slow and requires ongoing elimination of the neuromuscular blocker from plasma. For profound vecuronium-induced blockade in which no twitch recovery has occurred, administration of neostigmine, 70 µg/kg, produces an initial reversal that falls far short of adequate recovery.[571] Subsequent recovery is at the same rate as spontaneous recovery and is due to the decrease in plasma concentration of vecuronium as the drug is eliminated.[571] [587] Administration of a second dose of neostigmine has no further effect on recovery[571] because acetylcholinesterase is already maximally inhibited.
If the block at the time of neostigmine administration is sufficiently deep that adequate recovery does not occur within 10 minutes, the time at which full recovery of neuromuscular function will occur depends on the inherent duration of action of the neuromuscular blocker.[582] With drugs that have a long duration of action, this period of inadequate neuromuscular function can be 30 to 60 minutes or longer, whereas with drugs that have an intermediate duration of action, it will be much shorter (i.e., 15 to 30 minutes).[60]
Under conditions of moderate depth of blockade (such as two to three twitches palpable by TOF monitoring), the order of rapidity of antagonism of residual blockade by anticholinesterases is edrophonium > neostigmine > pyridostigmine. [585] [588] For this reason and because of its lesser atropine requirement, edrophonium regained popularity as an antagonist during the 1980s.[585] However, Rupp and coworkers[589] found that edrophonium is not as effective as neostigmine in antagonizing profound blockade of greater than 90% twitch depression (only one twitch palpable by TOF). Although increasing the edrophonium dose from 0.5 to 1.0 mg/kg increases its efficacy, neostigmine remains capable of more complete antagonism.[589] To be equivalent to 40 µg/kg neostigmine as an antagonist of profound vecuronium blockade, 1.5 mg/kg of edrophonium has to be administered.[590]
The relative potencies of edrophonium and neostigmine differ at various intensities of blockade ( Fig. 13-30 ).[591] Edrophonium becomes less potent with respect to neostigmine as the depth of blockade becomes more intense. In other words, the dose-response curves are not parallel and become increasingly divergent as the depth of blockade intensifies. This difference indicates that edrophonium may be less effective than neostigmine when antagonizing very deep levels of blockade.
Larger doses of anticholinesterases should antagonize neuromuscular blockade more rapidly and more completely than smaller doses do. This relationship is true up to the point of the maximum effective dose, beyond which further amounts of anticholinesterase will not produce any further antagonism. For neostigmine, this maximum dosage is in the range 60 to 80 µg/kg[571] [592] ; for edrophonium, the range is 1.0 to 1.5 mg/kg. [589] [590]
Figure 13-30
First twitch height (logit scale) versus dose (log scale)
10 minutes after administration of neostigmine and edrophonium given at either 1%
(99% block) or 10% (90% block) recovery of the first twitch. (Redrawn from
Donati F, Smith CE, Bevan DR: Dose-response relationships for edrophonium and neostigmine
as antagonists of moderate and profound atracurium blockade. Anesth Analg 68:13–19,
1989.)
Donati and associates[593] studied the reversal of 90% block induced by either dTc or pancuronium to demonstrate the relationship of the dose of neostigmine to the speed of reversal. They showed that increasingly greater amounts of antagonism of neuromuscular block occurred over the course of 10 minutes as the neostigmine dosage was increased from 5 to 50 µg/kg. Even after 50 µg/kg, however, twitch had recovered to only 80% of normal strength 10 minutes after neostigmine administration.
Mixing or combining antagonists is not advisable. Neostigmine and edrophonium do not potentiate each other; in fact, their effects in combination may not even be additive.[594] [595] Therefore, when inadequate reversal occurs, one should not be tempted to add a different anticholinesterase but should ensure only that the maximum dose of the original drug has been administered. Ventilation should then be supported until adequate neuromuscular function is achieved.
After administration of an anticholinesterase, two processes contribute to recovery of neuromuscular function. The first is antagonism induced by the effect of the anticholinesterase at the neuromuscular junction; the second is the natural process of decrease in the plasma concentration of the neuromuscular blocker (and hence the concentration of the neuromuscular blocker at the neuromuscular junction). [582] [587] Therefore, the more rapid the elimination of the neuromuscular blocker, the faster the recovery of adequate neuromuscular function after the administration of an antagonist ( Fig. 13-31 ).[596] A clear illustration of this principle is the difference in antagonizing a block induced by neuromuscular blockers with an intermediate versus a long duration of action. Plasma concentrations of drugs with an intermediate duration of action decrease more rapidly than do concentrations of drugs with a long duration of action,[245] and consequently
Figure 13-31
Comparative mean speed of antagonism by neostigmine of
neuromuscular blockade induced by long-acting drugs (doxacurium, pancuronium, pipecuronium),
intermediate-acting drugs (atracurium and others), and the short-acting drug mivacurium.
Antagonism is more rapid as processes of clearance increase (see text). (Redrawn
from Savarese JJ: Reversal of nondepolarizing blocks: More controversial than ever?
Review Course Lectures, 67th Congress, Cleveland, Ohio, International Anesthesia
Research Society, 1993.)
The interaction of spontaneous recovery and anticholinesterase-induced reversal of mivacurium is more complex. The rate of spontaneous recovery from mivacurium-induced blockade is more rapid than that from any other nondepolarizing neuromuscular blocker because of its rapid hydrolysis by butyrylcholinesterase. Neostigmine-induced reversal of mivacurium is similar to or faster than that of atracurium.[315] [599] During profound (<3% twitch recovery) mivacurium-induced blockade, administration of neostigmine may possibly prolong recovery.[600] Neostigmine has two major effects relevant to mivacurium. First, it inhibits acetylcholinesterase at the neuromuscular junction, thereby effectively increasing the acetylcholine concentration and facilitating recovery. Second, it inhibits butyrylcholinesterase, the enzyme responsible for the metabolism of mivacurium, and slows the normally rapid decrease in plasma concentration of mivacurium.[601] [602] In contrast, edrophonium is not as potent an inhibitor of butyrylcholinesterase, [601] [603] and it should have little effect on the metabolism of mivacurium. Provided that there is 10% recovery of the twitch response (one twitch in the TOF), either neostigmine, 20 to 40 µg/kg, or edrophonium, 0.3 to 0.5 mg/kg, will accelerate recovery from mivacurium.[579] [599] [604]
It has been suggested that routine administration of an anticholinesterase may often be omitted because spontaneous recovery from mivacurium is so rapid.[605] However, this strategy may lead to inadequate recovery and postoperative weakness unless at least 20 minutes is allowed for spontaneous recovery.[599] [604] As indicated earlier, administration of an anticholinesterase drug should probably be routine.[598]
Because mivacurium is metabolized by butyrylcholinesterase, recovery, in theory, may be made more rapid by the administration of exogenous human butyrylcholinesterase. Administration of purified human cholinesterase does produce some antagonism of mivacurium-induced blockade,[606] but it is ineffective in a profound block[601] and no better than edrophonium alone.[607] It may be justified to administer purified butyrylcholinesterase to patients homozygous for atypical butyrylcholinesterase who have a prolonged block,[320] [608] but this therapy has yet to be adequately tested and is expensive.
Several studies have documented that antagonism of residual blockade is actually retarded by anesthetizing concentrations of volatile anesthetics.[609] [610] [611] [612] [613] For example, Delisle and Bevan[609] showed that pancuronium reversal by neostigmine under enflurane anesthesia occurred more slowly than under nitrous oxide and intravenous anesthetics. It has even been suggested that the effect is different for different anesthetics and that sevoflurane may impede neostigmine-induced antagonism more than isoflurane does.[610] When compared with isoflurane anesthesia, the recovery variables are prolonged during desflurane or sevoflurane anesthesia.[614] [615] Withdrawal of the inhaled anesthetic at the end of surgery, with subsequent reduction of its enhancement of neuromuscular blockade, will speed pharmacologic reversal. [572]
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