Anesth Prog 35:43-47 1988
SCIENTIFIC ARTICLES
Reversal Agents in Sedation and Anestesia: A Review
This paper reviews the use of prototypic drugs for
reversal of the effects produced by anesthetic and
sedative agents. Efficacy and toxicity information
is presented for naloxone (as used to reverse
opioids), physostigmine (as used for reversal of
sedatives), and Flumazenil (a new specific
benzodiazepine receptor antagonist). Naloxone is
very useful and specific for reversing adverse and
life-threatening respiratory depression caused by
narcotic drugs and should be used in these
situations. Physostigmime has been advocated in
incremental doses for reversing sedative effects in
patients who are obtunded or depressed after
having received benzodiazepines, droperidol,
scopolamine, opioids, and phenothiazines.
Flumazenil has been shown to readily antagonize
the sedative, respiratory depressant, anxiolytic,
muscle relaxant, anticonvulsant, amnestic, and
anesthetic effects of the benzodiazepines; it
appears to have tremendous potential for use in
anesthesia, conscious sedation, and emergency
medicine when available.
O ne of the goals of the anesthesiologist is to render
the patient free of pain and anxiety for the
duration of a surgical or other therapeutic procedure with
a prompt return to baseline functioning when the proce-
dure is complete. To accomplish this task, however,
potent central nervous system depressant drugs must
Received June 26, 1987; accepted for publication November 6, 1987.
Address correspondence to Jay A. Anderson, D.D.S., M.D., Dept. of
Anesthesiology, NCMH 204H, School of Medicine, University of North
Carolina, Chapel Hill, NC 27514.
C 1988 by the American Dental Society of Anesthesiology
43
Jay A. Anderson, DDS, MD
Department of Anesthesiology,
School of Medicine, and Department
of Oral and Maxillofacial Surgery,
School of Dentistry, University of
North Carolina, Chapel Hill, North Carolina
often be used, the effects of which may linger far beyond
the time necessary for the procedure itself. In addition,
some patients unexpectedly display marked sensitivity to
these drugs and can be depressed for prolonged periods,
occasionally requiring pharmacologic or mechanical sup-
port of vital functions postoperatively. An ideal solution to
these situations would be the availability of drugs to
reverse the effects of the therapeutic drug (anesthetic)
when the anesthetic effect is no longer needed (ie, an
"anesthetic antidote"). To be useful, however, a reversal
drug should not possess significant adverse side effects of
its own. Several drugs have been advocated, evaluated,
and implemented clinically as reversal agents for drugs
used during anesthesia and sedation. These reversal
drugs generally fall into two categories: nonspecific ana-
leptic (arousal) agents and receptor specific antagonists.
The primary reversal agents that are used or have been
advocated for use in anesthesia include the anticholines-
terase agents (eg, neostigmine, edrophonium) for rever-
sal of the nondepolarizing muscle relaxants (eg, pancu-
ronium, vecuronium), the opioid receptor antagonist
naloxone, the nonspecific analeptic agents for reversal of
somnolence and/or anesthesia and, most recently, the
specific benzodiazepine receptor antagonist flumazenil.
This discussion will focus on those agents advocated for
reversing sedative effects of anesthetics-ie, all of the
above except the reversal of neuromuscular blockade.
NALOXONE
Naloxone (Narcan) is the most selective of the opioid
receptor antagonists. It has long been used to reverse the
undesirable side effects of the narcotic agents in emer-
gency medicine and anesthesia. Small doses will rapidly
antagonize narcotic-induced effects including respiratory
depression, analgesia, and euphoria. The primary indica-
tion for the use of naloxone in anesthesia and sedation is
ISSN 0003-3006/88/$3.50
44 Reversal Agents in Sedation and Anesthesia
the reversal of post- or intraoperative respiratory de-
pression that is felt to be due to narcotic administration.
Other uses for which it has been advocated include
"wake-up testing" during narcotic anesthesia, as an
adjunct to resuscitation of patients in shock and as a
treatment for postoperative rigidity.
Naloxone antagonizes the opioid effects that are medi-
ated by all of the opioid receptor subtypes, but to
differing degrees. The recent characterization of opioid
receptor subpopulations and animal studies suggest that
it should be possible to reverse the respiratory depressant
effects of narcotics without antagonizing the analgesic
effect by careful titration of naloxone.' In the future,
development of more specific antagonists may permit
selective antagonism of respiratory depression.
During sedation and anesthesia, naloxone is com-
monly used either as an emergency drug, to antagonize
unexpected and life-threatening respiratory depression,
or to reverse postoperative sedation produced by a drug
combination that includes an opioid. The usual dose
recommended is about 1 ug/kg, or 0.04-0.08 mg by
intravenous (IV) titration. The dose may be repeated after
5-10 minutes as needed. The duration of action of
naloxone is short (clinical duration about 30 minutes/
elimination half-life 1 hour) compared with that of the
doses of narcotics commonly used for anesthesia or
involved in overdose. Thus, the depressant effects of the
opioid may recur in a patient who was previously re-
versed. Patients must, therefore, be carefully observed
and may require readministration of naloxone. Subcu-
taneous or intramuscular injection of naloxone will pro-
duce a more prolonged effect and may help alleviate this
problem, but cannot be depended upon to totally elimi-
nate it.
For some time it was thought that naloxone had no
effects of its own in the absence of opioid reversal and it
was often used in a rather cavalier fashion. However,
many reports indicate that naloxone may have significant
effects, especially on the cardiovascular system, with or
without prior opioid administration. The complications
most frequently reported have included pulmonary
edema, hypertension, associated rupture of cerebral
aneurysm, cardiac dysrhythmias (ventricular and supra-
ventricular), cardiac arrest and sudden death.23 Many of
these problems have occurred in patients with no known
cardiovascular disease. Possible mechanisms for these
effects include the unmasking of severe pain or acute
physical dependence, a general analeptic effect, or a
sudden dramatic increase in circulating catechol-
amines.4'5 A specific drug interaction may occur when
naloxone is administered to a patient receiving the
antihypertensive agent clonidine. Clonidine is an alpha-2
receptor antagonist that decreases central sympathetic
outflow and decreases the amount of sympathetic neuro-
Anesth Prog 35:43-47 1988
transmitter released peripherally. The antihypertensive
effects of the drug can be antagonized by naloxone
producing sudden severe hypertension.6
Naloxone is very useful and specific for reversing
adverse and life-threatening respiratory depression
caused by narcotic drugs and should be used in these
situations. Naloxone, thus, belongs in every emergency
drug kit for settings in which an opioid will be used for
any reason. The use of naloxone to reverse the sedative
effects of narcotic techniques postoperatively must be
evaluated much more carefully, however, and should be
embarked upon with caution and careful consideration as
to whether the reversal of narcotic effects will actually be
beneficial to the patient. Certainly the drug should be
titrated slowly in small increments rather than given in a
bolus. Considering the presence of the endogenous
opioids (ie, endorphins and enkephalins), it is not surpris-
ing that large bolus doses of naloxone often result in a
patient who is nauseated, in pain, anxious and quite
uncomfortable due to the overzealous reversal of not
only the undesirable effects of the exogenously adminis-
tered narcotic, but also the beneficial physiologic effects
of the endogenous system. In light of the reported serious
side effects, the use of naloxone to indiscriminately
reverse the effects of an opioid that has been used to
produce sedation or anesthesia cannot be supported.
REVERSAL OF SEDATION
Several drugs have been advocated for reversing the
sedative effects of agents other than opioids. Until re-
cently, none of these were specific receptor antagonists
like naloxone, but rather, produce a nonspecific analeptic
or arousal effect that may antagonize sedation to some
extent. Some of the drugs that have been suggested for
their analeptic effects are physostigmine, caffeine, the-
ophylline (aminophylline), and doxapram. Case reports
and studies regarding the use of these drugs are inconsis-
tent, which is to be expected because their effects are
nonspecific. The principal situation in which these drugs
have been advocated is to overcome respiratory depres-
sion following anesthesia or sedation using central ner-
vous system depressant drugs such as benzodiazepines,
butyrophenones, or phenothiazines. The most com-
monly advocated of these agents is physostigmine.
Physostigmine
Physostigmine belongs to the anticholinesterase group of
drugs. It is a naturally occurring alkaloid and, unlike
neostigmine or edrophonium, is a tertiary amine. There-
Anesth Prog 35:43-47 1988
fore it readily crosses the blood-brain barrier and exerts
effects in the central nervous system. Physostigmine
competitively inhibits the action of acetylcholinesterase
that normally degrades acetylcholine. The presence of
physostigmine in the central nervous system therefore
increases the concentration of acetylcholine that acts as a
neurotransmitter in the brain as well as the parasym-
pathetic nervous system and the neuromuscular junction.
The increased acetylcholine concentration can specifi-
cally antagonize the central anticholinergic syndrome that
may be produced by drugs which penetrate the blood-
brain barrier and exert anticholinergic effects, such as
atropine, scopolamine, tricyclic antidepressants, and bu-
tyrophenones.
Physostigmine's ability to antagonize sedation is be-
lieved to be due to nonspecific central and arousal
produced by the increase in acetylcholine concentration.
It may also cause arousal by inhibition of neural phos-
phodiesterase that results in an increase in the concentra-
tion of cyclic AMP. This effect on phosphodiesterase is
similar to that produced by theophylline and caffeine.
The other anticholinesterases lack this property.
Physostigmine has been advocated in incremental
doses of 0.5-2 mg for reversing sedative effects in
patients who are obtunded or depressed after having
received benzodiazepines, droperidol, scopolamine, opi-
oids, and phenothiazines.7'8 Arthur and Hui9 recently
reported a case in which they were unexpectedly re-
quested to awaken a patient during a spinal operation so
that neurological testing could be done. The patient had
received morphine, scopolamine, and diazepam as a
premedicant and pentothal, fentanyl, nitrous oxide, and
halothane for maintenance of anesthesia. Thirty-five
minutes after all anesthetics had been discontinued, no
signs of arousal were evident even by EEG, which
continued to show an anesthetized pattern. Two mg of
physostigmine were given over two minutes, reportedly
resulting in awakening of the patient and a change in the
EEG pattern to awake pattem. Analgesia was reportedly
maintained because the patient remained comfortable
and cooperative (while intubated and prone) for neurolo-
gic testing. The patient subsequently had no recall of this
procedure.
Because most of the reports that support the use of
physostigmine as a reversal agent are case reports,
several investigators have attempted controlled, double-
blind trials to test the drug's efficacy. Garber et al"0 were
unable to demonstrate any improvement in level of
awareness or psychomotor function using 2 mg of physo-
stigmine plus 1 mg of atropine in patients sedated with IV
diazepam. Pandit et al"l were unable to demonstrate any
effect of physostigmine in reversing the sedative, psycho-
motor, or EEG effects produced by lorazepam. The only
difference in levels of sedation in this study were at 60
Anderson 45
minutes after physostigmine administration and were
attributed to the high incidence of nausea in the physo-
stigmine group. Bourke et al"2 tested physostigmine for
reversal of the respiratory depressant and psychomotor
effects produced by diazepam and morphine. They
found that physostigmine did not antagonize the respira-
tory depression produced by morphine or the psychomo-
tor dysfunction produced by diazepam. They did report
that physostigmine appeared to antagonize respiratory
depression (when produced) by diazepam. Spaulding et
al13 reported an apparent improvement in the level of
awareness in patients receiving 2 mg of physostigmine IV
after diazepam sedation, but measured a decrease in
ventilatory drive compared to placebo, demonstrated as
a decrease in the slope of the CO2 response curve
following physostigmine administration. They state that
physostigmine may reverse the sedation from ben-
zodiazepines while paradoxically producing worsening of
respiratory depression, that could potentially lead to
hypercarbia, hypoxia, and cardiac arrest. Other studies
have also reported conflicting results. From these trials it
appears that the nonspecific analeptic effect of physostig-
mine may produce (sometimes dramatic) arousal in
patients who have been sedated or anesthetized. The
effect is probably more consistent for benzodiazepines
than for narcotics and is certainly more profound when
somnolence is produced by the central anticholinergic
syndrome, where there is direct neurotransmitter interac-
tion. Physostigmine, therefore, may be indicated as an IV
reversal agent in specific instances where reversal of
sedation or respiratory depression is deemed necessary
or highly desirable. Physostigmine, however, cannot be
relied upon to produce the desired effect consistently.
This drug must be used carefully, weighing its benefits
against its potential for serious side effects. Because
acetylcholine functions as the neurotransmitter for several
types of receptors, including those of the parasympathetic
nervous system, physostigmine alone will consistantly
produce predictable parasympathomimetic side effects.
These include bradycardia, salivation, and sweating.
Nausea and vomiting are common, and other more
serious effects have been reported including severe hy-
pertension, ventricular dysrhythmias, and atrial fibrillation.
Some of the peripheral effects may be attenuated by the
concurrent administration of a quaternary anticholinergic
drug, such as glycopyrolate, but this will not effect central
actions such as nausea. Physostigmine should be admin-
istered slowly in small increments with EKG monitoring.
The duration of action of physostigmine is 35-45 mi-
nutes. Therefore if apparent reversal of sedation is ac-
complished with the drug, the patient must be carefully
observed for recurrence of sedation if longer acting drugs,
such as diazepam or lorazepam, were received, especially
in high doses.
46 Reversal Agents in Sedation and Anesthesia
Flumazenil
Fortunately, the search for a safer and better nonspecific
reversal agent may be over, at least for the ben-
zodiazepines, due to the introduction of flumazenil, a new
drug that is currently undergoing clinical trials in the
United States pending FDA approval for use. 14 Because
benzodiazepines are widely used for conscious sedation
and general anesthesia, the rapid and safe termination of
their effects following the completion of the therapeutic
procedure to return the patient to the preoperative level
of functioning and, therefore, permit discharge is highly
desirable. Flumazenil is an imidazobenzodiazepine that
has been shown to bind to the same central nervous
system receptor sites as the benzodiazepines in a specific
and reversible fashion. 15 It is, therefore, felt to represent a
competitive receptor antagonist for the benzodiazepines.
Accordingly, flumazenil has been shown to not reverse
the effects of opioids, barbiturates, alcohol, ketamine, or
other sedatives. The drug has been studied in animals
and in humans in Europe. It has been shown to readily
antagonize the sedative, respiratory depressant, anxioly-
tic, muscle relaxant, anticonvulsant, amnestic, and
anesthetic effects of the benzodiazepines.16 In patients
who had received benzodiazepines, including diazepam
and midazolam, for sedation, the administration of flu-
mazenil produced arousal usually within 60 seconds of IV
injection.17 When patients who had undergone general
anesthesia with benzodiazepines plus other agents were
given the drug, the majority awoke within one to two
minutes.18 Patients who were in a coma from a ben-
zodiazepine overdose awakened within one to five min-
utes of flumazenil administration.'9'20 The useful doses
reported range from 0.1-10 mg by IV titration. The
duration of the effect lasted from 30 minutes to two
hours. Patients awakened faster following bolus injec-
tions, whereas titration resulted in a more gradual re-
sponse. Flumazenil may possess limited agonist proper-
ties including mild anxiolytic and anticonvulsant effects.
Following extensive trials in Switzerland involving over
2200 patients, the dose recommended was 0.1 mg/
minute by IV titration with a maximum dose of 10 mg. A
minimum effective dose of 0.4 mg appears to be neces-
sary for reversal.
Toxicity studies in animals at Hoffman-LaRoche labo-
ratories using acute and chronic administration have
shown that flumazenil was well tolerated by all routes of
administration, with signs of toxicity reported only after
very high doses. No teratogenic or carcinogenic effects
were found. In some foreign human trials, patients
perceived doses of flumazenil up to 100 mg IV and up to
600 mg orally, obviously far in excess of the therapeutic
doses recommended, and were generally well tolerat-
ed.21 Reported adverse effects have included rare sei-
zures (primarily in patients who had received large doses
Anesth Prog 35:43-47 1988
of benzodiazepines to control status epilepticus), anxiety
reactions and precipitation of signs of acute withdrawal in
animals chronically receiving benzodiazepines. The side
effects most commonly reported were: nausea (4.6%),
vomiting (2.8%), anxiety (2.4%), discomfort (2%), crying
(1.4%), mild increase in heart rate (1.4%), tremor
(1.2%), involuntary movements (1.2%) and dizziness
(1%). No significant hemodynamic or cardiovascular
changes have been noted following flumazenil adminis-
tration.
Flumazenil is metabolized in the liver and excreted by
the kidneys. The half-life of flumazenil appears to be
between 0.83 and 1.5 hours, much shorter than any of
the benzodiazepines commonly used for sedation or
anesthesia.22 With the half-life of midazolam being ap-
proximately 2.4 hours and diazepam about 10 times
longer, the possibility exists for the recurrence of ben-
zodiazepine effects such as sedation or respiratory de-
pression after flumazenil has been eliminated. This is
somewhat concerning, especially in the case of ben-
zodiazepine overdose where readministration of flu-
mazenil will be needed. In the future, perhaps a specific
benzodiazepine antagonist with a longer duration of
action will be developed to circumvent this problem. For
conscious sedation and short general anesthetics, signifi-
cant recurrence of benzodiazepine effects should not be a
significant problem because the redistribution half-life
and therefore the clinical duration of action for the usual
doses of the benzodiazepines used during sedation and
anesthesia is much shorter than the elimination half-life.
This new specific benzodiazepine receptor antagonist
appears to have very few side effects when titrated in the
recommended dosage range, while producing effective
and prompt reversal of the sedation and other effects
produced by benzodiazepines. Flumazenil appears to
have tremendous potential for use in anesthesia, con-
scious sedation and emergency medicine in the near
future.
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