Department
of Anesthesia, Northwestern TJniversity
eywords: Benzodiazepines; relaxants.
opioi
s; reversal
Medica
School.
Chicago,
agents:
ske8etal muscle
I&.
Pharmacologic antagonists, which compete with agonists at their receptors, accelerate natural recovery from agonists so that their side effects can be curtailed. The antagonist shorter or longer than that of the agonist, an side effects. Anesthesiologists and nurse anesthetists use opioids, nondepolarizing skeletal muscle relaxants, and benzodiazepines in the operating room and other clinical settings; these drugs also are admi istered in emergency medicine, dentistry, and specialties that employ en scopy. The existence of antagonists that reverse the effects of these agonists implies that the an overdose, patient can be given too much agonist, can self-administer or can have an idiosyncratic reaction to a normal dose.
*Professor Address reprint requests to Dr. Fragen at the Department of Anesthesia, Northwestern University Medical School, Room 360, 303 East Superio; Street, Chicago, IL 606 11,
USA. ‘I: 4992 Butterworth-KIeinenanil
Skeletal muscle relaxants can be divided into depolarizing and nondepolarizing agents. Succinylcholine, t e primary depolarizing relaxant, is used mainly as a single injection to facilitate tracheal intubation. Given by infusion, succinylcholine can result in a phase I or phase II block. While a phase II block can be antagonized pharmacologically, a phase I block cannot be antagonized, and it is often difficu!k to tell how much block is in which phase. Thus, antagonists are rarely indicated today after succinylcholine. The short- and intermediate-acting nondepolarizing relaxants have generally replaced succinylchoiine by infusion to maintain surgical relaxation. Kondepolarizing muscle relaxants block the effect of acetylcholine at nicotinic receptors. As the relaxants are redistributed from their receptors and metabolized, their receptor concentration eventually decreases to the point where acetylcholine, after its release by impulses traveling down a motor nerve, can reach enough receptors to contract the muscle. Neuromuscular block is frequently monitored by stimulating a motor nerve and observing the decrease in twitch tension of the muscle it in-
5. Clin.
Anesth.,
vol. 4 (Suppl
I), September-/October
1992
Original
Contributions
nervates compared with a control (predrug) twitch or by comparing the fourth with the first twit& of trainof-four stimulation1 Before any decrease in twitch tension can be observed or measured, the muscle relaxant must occupy more than 70% of the receptors.’ By inference, therefore, up to 70% of the receptors can still be occupied by the muscle relaxant when the muscles are recovering from relaxant effects, when the twitch tension returns to predrug values, or the fourth twitch is equal to the first twitch. When at least 30% of the nicotinic receptors are available to acetylcholine, it is apparent that patients can cough, breathe deeply, and maintain normal minute ventilation. However, normal grip strengt the ability to lift one’s head for at least 5 seconds require more than 50% receptor availability. Although the 5-second head lift is the best clinical sign of adequate recovery from or reversal of relaxant effects, the patient may nonetheless lack the muscle power to perform other functions. For inpatients, further muscle function may be unimportant, but if we are to discharge outpatients expecting them, at minimum, to ambulate, a higher proportion of functioning receptors may be needed. The longer acting the muscle relaxant and the less spontaneous recovery is apparent at the end of sargery, the greater is the need to reverse residual muscle relaxation pharmacologically. Most outpatient surgery requires muscle relaxation only to facilitate trachea! intubation or for a short enough duration so that the intermediate-acting relaxants atracurlum or vecuronium or the short-acting relaxant mivacurium are sufficient (Table 1). Recommended intubating doses
Ee 1.
A Classification of Muscle Relaxants
Long acting
d-Tubocurarine Gallarnine Metocurine Pancuronium Pipecuronium Doxacurium Atracurium ecuronium ocuronium* SRorlt actin Mivacurium ~~t~a§~Q~~ acting
Succinylcholine
*Not pet available for clinical use.
BOS
J. Glin.
Plnesth.,
vol. 4
T&de
2.
Recommended
,4ntubating
Dose
I\Z X ED,,,)
Recovery Index of Muscle Relaxants for Admit Outpatient Surgery
and
Mivacurium atracurium Vecuronium Xocwronium*
0.115 0.3 0.1 0,6
*Not yet availabie for clinical use.
(2 X ED,,) and recovery indices for these muscle relaxants are shown in Table 2. The recovery rndexthe time from 25% to 75% recovery of twitch heightis a measure of the slope of spontaneous recovery from a muscle relaxant. Mivacurium may be the best choice of these drugs for outpatient surgery: its recovery slo that pharmacologic reversal may accelerate spontaneous reversal only by about 5 minutes.” Because mivactice so recently (March acurium entered clinical Z992), it is not yet clear w ther this drug needs pharmacologic reversal if at least one twitch of t trainof-four is evident at the time reversal is come fated. Depth of block and clinical signs of recovery at the end of anesthesia determine whether the inte ate-acting drugs need to be reversed. If any exists that spontaneous recovery is adequate, the residual block should be pharmacologically antagonized. The success of reversal will depend on depth of block, clinical recovery signs, choice of‘ antagonist, and its dose. Neostigmine and ~d~o~bo~i~~~, both anticholinesterases, are the two most frequently used antagonists. They act to inhibit the breakdown of acetylcholine so it can accumulate and overpower the muscle relaxant at the receptor. Either antagonist can be used with the intermediate- and short-acting muscle relaxants. Doses of the antagonists and t corresponding anticholinergics are shown Neostigmine appears to act more predictably than edrophonium after a vecuronium-induced deep block, but not after an atracm-iun-induced deep block. When the block recovers to the first or second twitch of the train-of-four, however, edro onium and neostigmine are equally effective, but ropbonium acts more i necessary to prevent rapidly. An anticholinergic muscarlnic cholinergic effects. ecause atracurium and vecuronium rarely cause side effects, antagonists are their primary effect.
(Suppl I), September/October 1992
Edropbonium Edrophonium
Neostigmine
(deep block)
0.5
0.07
1.0
0.07 -_
0.04
tagonists s, which diminish pain, are administered as analgesic components of general anesthesia or monitored anesth ’ care (MAC). They act at the mu, delta opioid receptors in the central kappa, sigma, nervous system.4 In addition to their primary effect of pain relief, they can cause a host of side effects: drowsiness, psychic sedation, dysphoria, respiratory depression, changes in heart rate and bloo itus, sphincter spasm, denausea, vomiting, er function, and, with longcreased bowel and term use, dependence or addiction. While morphine, meperidine, and other Iongeracting opioids are used to relieve postoperative pain and form an occasional component of inpatient anesthesia, fentanyl and its derivatives, sufentanil and alfentanil, more commonly serve both purposes in outpatients. These drugs may also be injected into the subarachnoid or epidural space to treat pain in inpatients after major surgery or administered via an implantable pump or dermal patch to treat chronic pain. Their primary effect, analgesia, does not require reversal, so a pharmacologic antagonist is necessary only to treat side effects, the most serious of which in erative period are drowsiness and respiratory depression. These two side effects, if unwanted or unsafe9 are the main indications for an opioid antagonist, although other opioid side effects can be antagonized as well if they prove troublesome. However, several fact s make it preferable to tiioids carefully an avoid antagonists. Antagonists may confer their own side effects: pulmonary edema and arrhythmias have been reported after naloxone administration5 Moreover, pain relief becomes more difficult once an antagonist is given because the opioid and its antagonist are competing at the receptor. When the patient is in pain, catecholamines that to hypertension and tachycardia are remay lea
-
0.015
leased. Antagonists may also precipitate withdrawal symptoms in chronic opioid users. When opioid side effects require reversal, either a pure antagonist-naloxone or nalmefene-can be injected, or a partial agonist-antagonist such as nalbuphine can be given. Nalbuphine’s potential advantages over naloxone are in its longer duration of action and its own analgesic properties. Nalbupbine should thus reduce opioid side effects while maintaining analgesia. Nalbuphine is usually titrate 2.5- to 5-mg doses to a maximum Naloxone is titrated intravenously in 2O- to 40-~9 doses up to 0.4 mg. If side effects are not reversed with 0.4 mg naloxone in the perio airway and ventilation should be s causes of the side effects sought. S half-life of naloxone is about 1 bour and the duration f clinical effects are likewise s e observed for signs of rena Nalmefene is an analog of naltrexone, with a duration of action four times longer than that of naloxone, an elimination half-life of 8 to 9 hours, and a volume of distribution of 10 llkg.fi,T Metabolized in the liver, nalmefene is excreted by the kidney. Five percent of the parent drug is excreted :unchanged and about 60% as the glucuronoside. The recommended IV dose of 0.5 to 1 mg may reverse respiratory depression without reversing analgesia; 1 to 2 mg may also reverse analgesia. Light-heade ness is the most common side effect seen after its se, occurring when a 6-mg or greater dose is given. cause outpatients are generally given the shorter-acting opioids, their side effects are easily reversed, when necessary, with nalbuphine or small, titrated doses of naloxone. Two potent opioid analgesics, A-3665 and CI87084B, are under investigation in the U.S.*,9 These opioids have very short half-lives and durations of effect. If they become available, concerns regarding currently available opioids may recede; these new drugs can be given by continuous infusion, and their primary and side effects both will dissipate rapidly
J. Clin. hnesth.,
vol. 4 (Suppi
1); September/October
!992
11
Original Contributions
when the infusion is stopped, obviating &be need for pharmacologic antagonists at the end of general anesthesia or MAC.
Anesthesiologists as well as other physicians use benzodiazepines-e.g; midazolam, diazepam, lorazePam-in low doses for sedation (calming); anterograde amnesia (lack of recall after administration); and, as the dose is increased, drowsiness (hypnosis). It has been postulated that hypnosis occurs with 60% to 90% receptor occupancy and that anxiolysis or sedation occurs with 28% to 30% occupancy. At high enough dosages, benzodiazepines can cause unconsciousness or induction of general anesthesia. Except when used for premeditation, midazolam is the preferred benzodiazepine: it does not cause venous irritation, and its duration of effect is shorter than that of other benzodiazepines at equivalent doses. The unwanted side effects of benzodiazepines include prolonged drowsiness; prolonged amnesia (particularly when it occurs in outpatients); respiratory depression; and dysphoria. Cardiovascular effects are usually mild, but hypotension can occur in some patients. While low-dose IV midazolam is frequently given to outpatients to produce sedation and slight drowsiness for MAC, prolonged recovery following higher doses generally precludes its use in outpatients to induce general anesthesia or to maintain hypnosis as a component of balanced anesthesia. Flumazenil (Figure I) is a specific benzodiazepine antagonist released for general use in the U.S. in March 1992, although it has been available elsewhere for several years. It can completely reverse almost all benzodiazepine effects in the currently recommended maximum dose of 1 mg or 10 ml.‘0 A water-soluble benzodiazepine, flumazenil is prepared in a IO-ml a
Figure
1. Structural
formula of flumazenil.
12s
J. Clin. Anesth., vol. 4 (Suppl I), September/October
pule containing 0.1 mg/ml. According to the package insert, the drug should be titrated in O.l- to 0.2-mg increments (I to 2 ml) until the undesirable benzodiazepine effects are reversed. Because a drug’s duration of action is dose related~ and because a I-mg dose causes no intrinsic side effects, I believe that the entire I-mg ampule should be injected IV if the decision is made to reverse a benzodiazepine. It has been suggested that careful titration may leave anxiolytic properties intact, but I do not know how one confirms this. Since faster administration can cause sudden arousal, excitement, or disorientation, 1 minute is allowed between each O.2-mg incremental dose. When a large benzodiazepine dose (an overdose) has been injected or administered inadvertently, antagonism can be maintained with a continuous infusion of 0.5 mg of flumazenil per hour.“~r* occasionally a benzodiazepine causes a paradoxical reaction-excitement rather than a calming effect-which flumazenil can also antagonize. Flumazenil is 40% to 50% protein bound. Its characteristically rapid decline in plasma concentration accounts for its short duration of effect: clearance is 54 to 67 l/hr, tl@fi is 0.8 to 1. I6 hours.‘3 Flumazenil is metabolized to free carboxylic acid and the corresponding glucuronoside. Although its clearance is decreased in patients with moderate hepatic dysfunction, its pharmacokinetics are unaltered by age, gender, or renal failure.r3 Because the antagonist can cause the patient to revert to the unmedicated condition, umazenil may induce seizures when benzodiazepines have been given as anticonvulsants or to decrease intracranial pressure. Flumazenil apparently has no effect on cerebral blood flow or cerebral metabolism.i4 In chronic benzodiazepine users, however, it can precipitate acute withdrawal symptoms, including seizures, that will increase cerebral blood flow. Injection of flu also cause seizures in a patient who presents with a mixed drug overdose that includes both a benzodiazepine and a tricyclic antidepressant. Administered to reverse benzodiazepine effects in patients with coronary artery disease, flumazenil caused no major changes in left ventricuiar systolic function or coronary hemodynamics, but left ventricular end-diastolic pressure increased toward normal, Thus it should be used cautiously in patients in whom this pressure is elevated.‘j Whether flumazenil co?npletelyreverses respiratory depression caused by benzodiazepines is ble.16 Midazolam, at a dose of 0. I.3 mgikg, decreased ventilation, tidal volume: minute ventilation, and of the carbon dioxide (CO?) rethe slope 1992
Role
sponse curve. A !-mg dose of flumazenil reversed the tidal volume and minute ventilation depression to control values, but did not change the slope of the CO, response curve (FZgures 2 and 3).17 Clinically sigiratory depression generally will not be present after benzodiazepine reversal with flumazenil unless other respiratory depressants are present or the antagonist wears off while there is enough agonist available to depress ventilation, an unlikely scenario with benzodiazepine use in the perioperative period. Amnesia, which is dose related, is another troublesome benzodiazepine effect that can reappear early to reverse. Flumazenil alone has no inon memory. Amnesia can be reversed after small sedative doses,18 but it recurs after larger doses of midazolam. Outpatients who have been given benzodiazepines and flumazenil should therefore be given written instructions, be accompanied home by sible adult, and be treated as if they had not a resp a benzodiazepine antagonist. seceiv Elumazenii was used successfully in children to speed up recovery from midazolam-induced general anesthesia (Figure 4). Children who recovered spontaneously took three times as long to open their eyes orientation. The required flumazenil dose weakly with weight and did not correlate with age an 3- to 12-year-old children.ls When flumazenil was given to reverse benzodiazepine effects after midazolam induction of general drowsiness and psychomotor perforanesthesia,
m
FLUMAENIL
0
PRE-
POST-
3
0s reversal agents: Fragen
30
ure 3. Slope of the CO, response curve (iimrnimm Mg) pre- and postmidazolam as well as 3,30,60, and 120 minutes after ffumazenii or placebo. There were no significant differences between groups. (*p
of Anesthesia, Northwestern TJniversity
eywords: Benzodiazepines; relaxants.
opioi
s; reversal
Medica
School.
Chicago,
agents:
ske8etal muscle
I&.
Pharmacologic antagonists, which compete with agonists at their receptors, accelerate natural recovery from agonists so that their side effects can be curtailed. The antagonist shorter or longer than that of the agonist, an side effects. Anesthesiologists and nurse anesthetists use opioids, nondepolarizing skeletal muscle relaxants, and benzodiazepines in the operating room and other clinical settings; these drugs also are admi istered in emergency medicine, dentistry, and specialties that employ en scopy. The existence of antagonists that reverse the effects of these agonists implies that the an overdose, patient can be given too much agonist, can self-administer or can have an idiosyncratic reaction to a normal dose.
*Professor Address reprint requests to Dr. Fragen at the Department of Anesthesia, Northwestern University Medical School, Room 360, 303 East Superio; Street, Chicago, IL 606 11,
USA. ‘I: 4992 Butterworth-KIeinenanil
Skeletal muscle relaxants can be divided into depolarizing and nondepolarizing agents. Succinylcholine, t e primary depolarizing relaxant, is used mainly as a single injection to facilitate tracheal intubation. Given by infusion, succinylcholine can result in a phase I or phase II block. While a phase II block can be antagonized pharmacologically, a phase I block cannot be antagonized, and it is often difficu!k to tell how much block is in which phase. Thus, antagonists are rarely indicated today after succinylcholine. The short- and intermediate-acting nondepolarizing relaxants have generally replaced succinylchoiine by infusion to maintain surgical relaxation. Kondepolarizing muscle relaxants block the effect of acetylcholine at nicotinic receptors. As the relaxants are redistributed from their receptors and metabolized, their receptor concentration eventually decreases to the point where acetylcholine, after its release by impulses traveling down a motor nerve, can reach enough receptors to contract the muscle. Neuromuscular block is frequently monitored by stimulating a motor nerve and observing the decrease in twitch tension of the muscle it in-
5. Clin.
Anesth.,
vol. 4 (Suppl
I), September-/October
1992
Original
Contributions
nervates compared with a control (predrug) twitch or by comparing the fourth with the first twit& of trainof-four stimulation1 Before any decrease in twitch tension can be observed or measured, the muscle relaxant must occupy more than 70% of the receptors.’ By inference, therefore, up to 70% of the receptors can still be occupied by the muscle relaxant when the muscles are recovering from relaxant effects, when the twitch tension returns to predrug values, or the fourth twitch is equal to the first twitch. When at least 30% of the nicotinic receptors are available to acetylcholine, it is apparent that patients can cough, breathe deeply, and maintain normal minute ventilation. However, normal grip strengt the ability to lift one’s head for at least 5 seconds require more than 50% receptor availability. Although the 5-second head lift is the best clinical sign of adequate recovery from or reversal of relaxant effects, the patient may nonetheless lack the muscle power to perform other functions. For inpatients, further muscle function may be unimportant, but if we are to discharge outpatients expecting them, at minimum, to ambulate, a higher proportion of functioning receptors may be needed. The longer acting the muscle relaxant and the less spontaneous recovery is apparent at the end of sargery, the greater is the need to reverse residual muscle relaxation pharmacologically. Most outpatient surgery requires muscle relaxation only to facilitate trachea! intubation or for a short enough duration so that the intermediate-acting relaxants atracurlum or vecuronium or the short-acting relaxant mivacurium are sufficient (Table 1). Recommended intubating doses
Ee 1.
A Classification of Muscle Relaxants
Long acting
d-Tubocurarine Gallarnine Metocurine Pancuronium Pipecuronium Doxacurium Atracurium ecuronium ocuronium* SRorlt actin Mivacurium ~~t~a§~Q~~ acting
Succinylcholine
*Not pet available for clinical use.
BOS
J. Glin.
Plnesth.,
vol. 4
T&de
2.
Recommended
,4ntubating
Dose
I\Z X ED,,,)
Recovery Index of Muscle Relaxants for Admit Outpatient Surgery
and
Mivacurium atracurium Vecuronium Xocwronium*
0.115 0.3 0.1 0,6
*Not yet availabie for clinical use.
(2 X ED,,) and recovery indices for these muscle relaxants are shown in Table 2. The recovery rndexthe time from 25% to 75% recovery of twitch heightis a measure of the slope of spontaneous recovery from a muscle relaxant. Mivacurium may be the best choice of these drugs for outpatient surgery: its recovery slo that pharmacologic reversal may accelerate spontaneous reversal only by about 5 minutes.” Because mivactice so recently (March acurium entered clinical Z992), it is not yet clear w ther this drug needs pharmacologic reversal if at least one twitch of t trainof-four is evident at the time reversal is come fated. Depth of block and clinical signs of recovery at the end of anesthesia determine whether the inte ate-acting drugs need to be reversed. If any exists that spontaneous recovery is adequate, the residual block should be pharmacologically antagonized. The success of reversal will depend on depth of block, clinical recovery signs, choice of‘ antagonist, and its dose. Neostigmine and ~d~o~bo~i~~~, both anticholinesterases, are the two most frequently used antagonists. They act to inhibit the breakdown of acetylcholine so it can accumulate and overpower the muscle relaxant at the receptor. Either antagonist can be used with the intermediate- and short-acting muscle relaxants. Doses of the antagonists and t corresponding anticholinergics are shown Neostigmine appears to act more predictably than edrophonium after a vecuronium-induced deep block, but not after an atracm-iun-induced deep block. When the block recovers to the first or second twitch of the train-of-four, however, edro onium and neostigmine are equally effective, but ropbonium acts more i necessary to prevent rapidly. An anticholinergic muscarlnic cholinergic effects. ecause atracurium and vecuronium rarely cause side effects, antagonists are their primary effect.
(Suppl I), September/October 1992
Edropbonium Edrophonium
Neostigmine
(deep block)
0.5
0.07
1.0
0.07 -_
0.04
tagonists s, which diminish pain, are administered as analgesic components of general anesthesia or monitored anesth ’ care (MAC). They act at the mu, delta opioid receptors in the central kappa, sigma, nervous system.4 In addition to their primary effect of pain relief, they can cause a host of side effects: drowsiness, psychic sedation, dysphoria, respiratory depression, changes in heart rate and bloo itus, sphincter spasm, denausea, vomiting, er function, and, with longcreased bowel and term use, dependence or addiction. While morphine, meperidine, and other Iongeracting opioids are used to relieve postoperative pain and form an occasional component of inpatient anesthesia, fentanyl and its derivatives, sufentanil and alfentanil, more commonly serve both purposes in outpatients. These drugs may also be injected into the subarachnoid or epidural space to treat pain in inpatients after major surgery or administered via an implantable pump or dermal patch to treat chronic pain. Their primary effect, analgesia, does not require reversal, so a pharmacologic antagonist is necessary only to treat side effects, the most serious of which in erative period are drowsiness and respiratory depression. These two side effects, if unwanted or unsafe9 are the main indications for an opioid antagonist, although other opioid side effects can be antagonized as well if they prove troublesome. However, several fact s make it preferable to tiioids carefully an avoid antagonists. Antagonists may confer their own side effects: pulmonary edema and arrhythmias have been reported after naloxone administration5 Moreover, pain relief becomes more difficult once an antagonist is given because the opioid and its antagonist are competing at the receptor. When the patient is in pain, catecholamines that to hypertension and tachycardia are remay lea
-
0.015
leased. Antagonists may also precipitate withdrawal symptoms in chronic opioid users. When opioid side effects require reversal, either a pure antagonist-naloxone or nalmefene-can be injected, or a partial agonist-antagonist such as nalbuphine can be given. Nalbuphine’s potential advantages over naloxone are in its longer duration of action and its own analgesic properties. Nalbupbine should thus reduce opioid side effects while maintaining analgesia. Nalbuphine is usually titrate 2.5- to 5-mg doses to a maximum Naloxone is titrated intravenously in 2O- to 40-~9 doses up to 0.4 mg. If side effects are not reversed with 0.4 mg naloxone in the perio airway and ventilation should be s causes of the side effects sought. S half-life of naloxone is about 1 bour and the duration f clinical effects are likewise s e observed for signs of rena Nalmefene is an analog of naltrexone, with a duration of action four times longer than that of naloxone, an elimination half-life of 8 to 9 hours, and a volume of distribution of 10 llkg.fi,T Metabolized in the liver, nalmefene is excreted by the kidney. Five percent of the parent drug is excreted :unchanged and about 60% as the glucuronoside. The recommended IV dose of 0.5 to 1 mg may reverse respiratory depression without reversing analgesia; 1 to 2 mg may also reverse analgesia. Light-heade ness is the most common side effect seen after its se, occurring when a 6-mg or greater dose is given. cause outpatients are generally given the shorter-acting opioids, their side effects are easily reversed, when necessary, with nalbuphine or small, titrated doses of naloxone. Two potent opioid analgesics, A-3665 and CI87084B, are under investigation in the U.S.*,9 These opioids have very short half-lives and durations of effect. If they become available, concerns regarding currently available opioids may recede; these new drugs can be given by continuous infusion, and their primary and side effects both will dissipate rapidly
J. Clin. hnesth.,
vol. 4 (Suppi
1); September/October
!992
11
Original Contributions
when the infusion is stopped, obviating &be need for pharmacologic antagonists at the end of general anesthesia or MAC.
Anesthesiologists as well as other physicians use benzodiazepines-e.g; midazolam, diazepam, lorazePam-in low doses for sedation (calming); anterograde amnesia (lack of recall after administration); and, as the dose is increased, drowsiness (hypnosis). It has been postulated that hypnosis occurs with 60% to 90% receptor occupancy and that anxiolysis or sedation occurs with 28% to 30% occupancy. At high enough dosages, benzodiazepines can cause unconsciousness or induction of general anesthesia. Except when used for premeditation, midazolam is the preferred benzodiazepine: it does not cause venous irritation, and its duration of effect is shorter than that of other benzodiazepines at equivalent doses. The unwanted side effects of benzodiazepines include prolonged drowsiness; prolonged amnesia (particularly when it occurs in outpatients); respiratory depression; and dysphoria. Cardiovascular effects are usually mild, but hypotension can occur in some patients. While low-dose IV midazolam is frequently given to outpatients to produce sedation and slight drowsiness for MAC, prolonged recovery following higher doses generally precludes its use in outpatients to induce general anesthesia or to maintain hypnosis as a component of balanced anesthesia. Flumazenil (Figure I) is a specific benzodiazepine antagonist released for general use in the U.S. in March 1992, although it has been available elsewhere for several years. It can completely reverse almost all benzodiazepine effects in the currently recommended maximum dose of 1 mg or 10 ml.‘0 A water-soluble benzodiazepine, flumazenil is prepared in a IO-ml a
Figure
1. Structural
formula of flumazenil.
12s
J. Clin. Anesth., vol. 4 (Suppl I), September/October
pule containing 0.1 mg/ml. According to the package insert, the drug should be titrated in O.l- to 0.2-mg increments (I to 2 ml) until the undesirable benzodiazepine effects are reversed. Because a drug’s duration of action is dose related~ and because a I-mg dose causes no intrinsic side effects, I believe that the entire I-mg ampule should be injected IV if the decision is made to reverse a benzodiazepine. It has been suggested that careful titration may leave anxiolytic properties intact, but I do not know how one confirms this. Since faster administration can cause sudden arousal, excitement, or disorientation, 1 minute is allowed between each O.2-mg incremental dose. When a large benzodiazepine dose (an overdose) has been injected or administered inadvertently, antagonism can be maintained with a continuous infusion of 0.5 mg of flumazenil per hour.“~r* occasionally a benzodiazepine causes a paradoxical reaction-excitement rather than a calming effect-which flumazenil can also antagonize. Flumazenil is 40% to 50% protein bound. Its characteristically rapid decline in plasma concentration accounts for its short duration of effect: clearance is 54 to 67 l/hr, tl@fi is 0.8 to 1. I6 hours.‘3 Flumazenil is metabolized to free carboxylic acid and the corresponding glucuronoside. Although its clearance is decreased in patients with moderate hepatic dysfunction, its pharmacokinetics are unaltered by age, gender, or renal failure.r3 Because the antagonist can cause the patient to revert to the unmedicated condition, umazenil may induce seizures when benzodiazepines have been given as anticonvulsants or to decrease intracranial pressure. Flumazenil apparently has no effect on cerebral blood flow or cerebral metabolism.i4 In chronic benzodiazepine users, however, it can precipitate acute withdrawal symptoms, including seizures, that will increase cerebral blood flow. Injection of flu also cause seizures in a patient who presents with a mixed drug overdose that includes both a benzodiazepine and a tricyclic antidepressant. Administered to reverse benzodiazepine effects in patients with coronary artery disease, flumazenil caused no major changes in left ventricuiar systolic function or coronary hemodynamics, but left ventricular end-diastolic pressure increased toward normal, Thus it should be used cautiously in patients in whom this pressure is elevated.‘j Whether flumazenil co?npletelyreverses respiratory depression caused by benzodiazepines is ble.16 Midazolam, at a dose of 0. I.3 mgikg, decreased ventilation, tidal volume: minute ventilation, and of the carbon dioxide (CO?) rethe slope 1992
Role
sponse curve. A !-mg dose of flumazenil reversed the tidal volume and minute ventilation depression to control values, but did not change the slope of the CO, response curve (FZgures 2 and 3).17 Clinically sigiratory depression generally will not be present after benzodiazepine reversal with flumazenil unless other respiratory depressants are present or the antagonist wears off while there is enough agonist available to depress ventilation, an unlikely scenario with benzodiazepine use in the perioperative period. Amnesia, which is dose related, is another troublesome benzodiazepine effect that can reappear early to reverse. Flumazenil alone has no inon memory. Amnesia can be reversed after small sedative doses,18 but it recurs after larger doses of midazolam. Outpatients who have been given benzodiazepines and flumazenil should therefore be given written instructions, be accompanied home by sible adult, and be treated as if they had not a resp a benzodiazepine antagonist. seceiv Elumazenii was used successfully in children to speed up recovery from midazolam-induced general anesthesia (Figure 4). Children who recovered spontaneously took three times as long to open their eyes orientation. The required flumazenil dose weakly with weight and did not correlate with age an 3- to 12-year-old children.ls When flumazenil was given to reverse benzodiazepine effects after midazolam induction of general drowsiness and psychomotor perforanesthesia,
m
FLUMAENIL
0
PRE-
POST-
3
0s reversal agents: Fragen
30
ure 3. Slope of the CO, response curve (iimrnimm Mg) pre- and postmidazolam as well as 3,30,60, and 120 minutes after ffumazenii or placebo. There were no significant differences between groups. (*p
