Reversal Agents in Sedation and Anestesia: A Review

Transcription

1 Anesth Prog 35: SCIENTIFIC ARTICLES Reversal Agents in Sedation and Anestesia: A Review 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 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 procedure is complete. To accomplish this task, however, potent central nervous system depressant drugs must Received June 26, 1987; accepted for publication November 6, 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 C 1988 by the American Dental Society of Anesthesiology 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 support 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 analeptic (arousal) agents and receptor specific antagonists. The primary reversal agents that are used or have been advocated for use in anesthesia include the anticholinesterase agents (eg, neostigmine, edrophonium) for reversal of the nondepolarizing muscle relaxants (eg, pancuronium, 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 emergency medicine and anesthesia. Small doses will rapidly antagonize narcotic-induced effects including respiratory depression, analgesia, and euphoria. The primary indication for the use of naloxone in anesthesia and sedation is ISSN /88/$

2 44 Reversal Agents in Sedation and Anesthesia the reversal of post- or intraoperative respiratory depression 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 mediated 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 commonly 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 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 reversed. Patients must, therefore, be carefully observed and may require readministration of naloxone. Subcutaneous or intramuscular injection of naloxone will produce a more prolonged effect and may help alleviate this problem, but cannot be depended upon to totally eliminate 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 supraventricular), 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 catecholamines.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 neurotransmitter 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 surprising 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 administered 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 Anesth Prog 35: Several drugs have been advocated for reversing the sedative effects of agents other than opioids. Until recently, 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, theophylline (aminophylline), and doxapram. Case reports and studies regarding the use of these drugs are inconsistent, which is to be expected because their effects are nonspecific. The principal situation in which these drugs have been advocated is to overcome respiratory depression following anesthesia or sedation using central nervous system depressant drugs such as benzodiazepines, butyrophenones, or phenothiazines. The most commonly 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-

3 Anesth Prog 35: Anderson 45 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 parasympathetic nervous system and the neuromuscular junction. The increased acetylcholine concentration can specifically antagonize the central anticholinergic syndrome that may be produced by drugs which penetrate the bloodbrain barrier and exert anticholinergic effects, such as atropine, scopolamine, tricyclic antidepressants, and butyrophenones. Physostigmine's ability to antagonize sedation is believed to be due to nonspecific central and arousal produced by the increase in acetylcholine concentration. It may also cause arousal by inhibition of neural phosphodiesterase that results in an increase in the concentration 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 mg for reversing sedative effects in patients who are obtunded or depressed after having received benzodiazepines, droperidol, scopolamine, opioids, and phenothiazines.7'8 Arthur and Hui9 recently reported a case in which they were unexpectedly requested 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 neurologic 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, doubleblind 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 physostigmine 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, psychomotor, or EEG effects produced by lorazepam. The only difference in levels of sedation in this study were at 60 minutes after physostigmine administration and were attributed to the high incidence of nausea in the physostigmine 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 respiratory depression produced by morphine or the psychomotor 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 benzodiazepines 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 physostigmine 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 interaction. 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 hypertension, 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 administered slowly in small increments with EKG monitoring. The duration of action of physostigmine is minutes. Therefore if apparent reversal of sedation is accomplished 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.

4 46 Reversal Agents in Sedation and Anesthesia Anesth Prog 35: Flumazenil Fortunately, the search for a safer and better nonspecific reversal agent may be over, at least for the benzodiazepines, 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, anxiolytic, 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 flumazenil 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 benzodiazepine overdose awakened within one to five minutes of flumazenil administration.'9'20 The useful doses reported range from mg by IV titration. The duration of the effect lasted from 30 minutes to two hours. Patients awakened faster following bolus injections, whereas titration resulted in a more gradual response. Flumazenil may possess limited agonist properties 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 necessary for reversal. Toxicity studies in animals at Hoffman-LaRoche laboratories 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 tolerated.21 Reported adverse effects have included rare seizures (primarily in patients who had received large doses 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 administration. 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 approximately 2.4 hours and diazepam about 10 times longer, the possibility exists for the recurrence of benzodiazepine effects such as sedation or respiratory depression after flumazenil has been eliminated. This is somewhat concerning, especially in the case of benzodiazepine overdose where readministration of flumazenil 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, significant 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, conscious sedation and emergency medicine in the near future. REFERENCES 1. Hensel JI, Albrecht RF, Miletich DJ: The reversal of morphine mediated respiratory depression but not analgesia in rats. 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