CASE REPORTS
The reports presented are of my own patients or were reported to me by other practitioners. They represent over 200 cases of sedation and are presented to illustrate the types of problems we have seen and how they were controlled. The worst case scenario for most sedation is a respiratory depression and/or respiratory obstruction. In this worst case, a patient's exchange of gasses is inadequate to carry adequate O2 to the blood or remove CO2. The levels of O2 in the arterial blood would fall as would the O2 perfussion to tissues, particularly the brain. This depression would allow an increase in CO2 levels and thus a lowering of the pH of the blood. Triazolam has shown very little tendency to depress respiration or affect circulation. Generally speaking, however, and to reiterate my earlier comments, I am concerned when someone tends to sleep since if they are not awake, how do we know if they are under general anesthesia? The most common occurrence precipitating an anesthesia emergency is respiratory insufficiency. For this reason I am more comfortable when working on a conscious patient who is being monitored by a pulse oximeter with the alarm set to go off for any reading below 90% saturation.
Patient No. 1
The first case report is a 34 year old black female ASA 1. She was moderately overweight and had a rather short neck. She had worked the night before her appointment in a manufacturing plant and had been about 36 hours without sleep. I administered our usual dose for her weight. Thirty (30) minutes later she was noticeably more relaxed. We started her dentistry at 45 minutes and did operative dentistry for about 1 hour. She did fine. Her blood pressure, pulse rate, and respiration were normal. Her pulse oximeters reading ranged between 93 - 97%. At the close of the procedure she tended to sleep if we did not keep talking to her. Several times her head would drop on her chest and she would partially occlude her airway and snore. At these times her SAO2 would slowly fall to 87% over several minutes and she would then take a deep breath and return the saturation to the 93-97% range. We kept her in the dental chair for the next hour until she stopped obstructing and was noticeably less sedated. Her husband took her home with instructions to watch her and call if she had any problems. I called and checked on her several times that evening. She did fine. I was concerned about her obstructing her airway because of her body weight and short neck. Her husband reported that she normally snored when she slept.
Patient No. 2
The second patient was a 40 year old white female. She had been an IV patient for a number of years because of her dental phobia. She was given a modest dose of triazolam. She was noticeably relaxed by 30 minutes and we started her procedure at the 45 minute point. She tended to sleep if left unstimulated but would open her eyes and follow directions if she was spoken to. Her oxygen saturation stayed greater than 95%, her blood pressure and pulse rate stayed constant at pre-operative levels. We kept her in the dental office an extra hour and by that time she was staying awake. She was dismissed to an adult with directions to keep her awake and call if there were any problems.
Patient No. 3
The third patient was a 15 month old, 25 pound Asian female, a recent immigrant who had severe baby bottle caries. Our oral exam was very difficult and was confined to a simple visual exam. We attempted to treat her with 0.125 mg of triazolam as she was nearly uncontrollable. The treatment was somewhat complicated by her lack of understanding of English. We had a parent in the operatory to translate; however, little communication took place due to her age, and lack of control. For the second appointment we used 0.25 mg. of triazolam. She cried and moved some during treatment, but we were able to complete several stainless steel crowns. At the close of the appointment, 100 minutes after administering the drug, she tended to sleep although would awaken if verbally stimulated. Her pulse rate stayed constant at the pre-op levels and her O2 saturation stayed greater than 95% without supplemental oxygen. If left alone, however, she laid very still and slept. Two and a half (2 1/2) hours after drug administration she sat up and told her father she wanted to go home. We again gave directions to observe her the rest of the afternoon and call if she did not stay awake. Her father reported that she went home and watched TV without sleeping.
Patient No. 4
A seven year old was sedated for dental treatment by a pediatric dentist. The patient left the office able to walk holding the hand of her mother. She went home and tended to sleep if left alone. The dentist's home phone line was out of order that evening. After trying to reach the dentist, her mother became concerned and called a local emergency room who told her to watch the patient and that triazolam was not approved for use with children. The mother then called poison control and was again told that triazolam should not be used with children. The dentist relieved the mother's concerns when she reached him in the office the next day.
Patient No. 5
A 40 year old black male about 6'1" tall and 230 pounds had an uneventful sedation. At the close of the case, when he was judged to be ready to leave, his wife, a rather petite woman of 5'6," was brought in and given post-op instructions. At this time she mentioned they would be taking a public bus home. Because I was concerned about her being able to help the patient on and off the bus, we kept him an extra hour to assure us that his wife would not have any problem getting him home. We did not insist that the patient be transported by auto.
FLAMEZINAL, Romazcon
It would be a great advantage to have a drug that would reverse the effects of any drug we use. This is particularly true of any drug that requires excretion or metabolism to be deactivated. When using drugs intravenously, small test doses can be given and augmented as necessary to achieve the desired effect. These test doses go directly to the CNS and show their effect. They are then redistributed to the rest of the tissues of the body, effectively diluting the effect in the case of an overdose or sensitivity to an agent. Because it is impossible to titrate for effect when using oral drugs, it takes a considerable time before it is obvious we have a problem and redistribution and saturation of the other tissues has already taken place and are of little aid. In the case of overdose, there is little we can do except treat the symptoms of the overdose, and support respiration and circulation. For this reason, a reversal agent for oral drugs is very desirable.
History
In 1974, Haefely hypothesized that benzodiazepines act by increasing the effectiveness of the most important inhibitory neurotransmitter, GABA. In 1976 it was shown that diazepam bound selectively to certain brain proteins at the benzodiazepine receptor sites and that they made GABA more effective. They produced several compounds that had a greater affinity for this site than diazepam. One of these, flamezinal, was selected in 1979 as an antagonist for clinical trials.
In early 1992, the Hoffman La Rouche company introduced to the U.S. market a benzodiazepine reversal agent, MaziconŠ, flumazenil, ethyl 6-fluoro-6,6-dihydro-5-methyl-6-oxo-4h-imidazo (l,5-a)(1,4) benzodiazepine-3-carboxylate. This agent has been in use in other parts of the world for some time and has proven very important in treating overdoses and reversing the effects of benzodiazepine. Flumazenil displaces benzodiazepine drugs from their receptor site, reversing their sedative action.
Normal dosages of this drug are reported to be .007 and .014 mg/kg. The lethal dose in mice and rats is 62.5 and 125 mg/kg. Another study suggested that 3000 times the therapeutic dose could be given with only minor effects. It has been tested up to 200 mg. given IV and orally. In the case of oral dosages, only 18% are active as it is oxidized in the first pass through the liver.
The following quotation is from a letter from M. L. Bergamo, M.D., Assistant Director, Professional Services, Roache Laboratories, dated February 27, 1992. "Flumazenil is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose."
"Doses of approximately .1 to .2 mg (corresponding to peak plasma levels of 3 to 6 ng/mL) produce antagonism, whereas higher doses of .4 to 1.0 mg (peak plasma levels of 12 to 28 mg/mL) usually produce complete antagonism in patients that have received the usual sedating doses of benzodiazepines. The onset of reversal is usually evident within one to two minutes, with peak effects occurring six to ten minutes after a single intravenous injection. The duration and degree of reversal is also related to the plasma concentration of the sedating benzodiazepine." "Most patients with benzodiazepine overdose will respond to a cumulative dose of 1 to 3 mg of flumazenil and doses beyond 3 mg do not reliably produce additional effects. On rare occasions, patients with a partial response at 3.0 mg may require additional titration up to a total dose of 5.0 mg."
"If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg, the major cause of sedation is likely not to be due to benzodiazepines. ... In management of suspected overdose, 497 patients received flumazenil, 299 proved to have taken a benzodiazepine, 83% responded by an improvement in the level of consciousness. 77% responded to a total dose of 1.0 to 3.0 mg. "
"In the event of resedation repeated doses may be given at 20 minute intervals if needed. For repeat treatment, no more than 1.0 (given as .5 mg/min) should be given at any one time and no more than 3.0 mg should be given in any one hour."
"In the overdose treated patient, reversal of sedation was associated with an increased frequency of symptoms of CNS excitation (agitation or anxiety) which were treated in 1% to 3% of the cases. Serious side effects were uncommon, but six seizures were observed in 446 patients treated with Mazicon in these studies. Four of the six patients who experienced seizures had ingested a large dose of cyclic antidepressants."
"Resedation has been observed in 1% to 3% of the patients in the clinical trials. Resedation is least likely in cases where Mazicon is given to reverse a low dose of a short-acting benzodiazepine (<10 mg midazolam), and most likely in cases where a large single or cumulative dose of a benzodiazepine has been given in the course of a long procedure along with neuromuscular blocking agents and multiple anesthetic agents."
Adverse effects
"The most frequently associated adverse events reported during clinical trials were nausea, vomiting, dizziness (vertigo, ataxia), agitation (anxiety, nervousness), emotional lability (euphoria, abnormal crying, abnormal tears), cutaneous vasodilation (sweating, flushing, hot flashes), injection site pain, injection site reaction, fatigue (asthenia, malaise), abnormal vision (visual field defect, diplopia), hyposthesia (sensation abnormal, paresthesia), and headache."
Mechanism of Action
Flumazenil competitively interacts with other benzodiazepine drugs at the GABA "chloride channel receptor sites in the CNS, particularly in the cortex, limbic lobe, and spinal cord. It has no effect on peripheral receptors."
Metabolism
"Flumazenil is quickly and completely metabolized in the liver by hepatic microsomal oxidation." It is converted into inactive acid or glucuronide metabolites. "Less than 0.2% is excreted unchanged in the urine.
Pharmacokinetics
The absorption half-life of oral flumazenil is about 0.3 hours. Peak plasma concentrations occurred 20 to 90 minutes after administration. When given orally the drug is absorbed from the GI system and passes via the portal circulation through the liver before becoming available to the CNS. Only about 16% becomes available to the circulatory system. 200 mg oral doses gave similar blood levels as 40 mg doses given intravenously. Rapid uptake by the brain has been shown to be a 3:1 ratio brain-to-blood. It has been shown to be distributed by the cerebral vasculature and taken up by gray-matter structures within 1 to 2 minutes if given intravenously. Maximal cerebral concentrations are attained in 5 to 8 minutes. Binding was greatest in the medial-occipital cerebral cortex and to a lesser extent in the cerebellum and pons. It conformed to the GABA receptor sites of the brain and was cleared from the body in 4 hours.
Pharmacology
Flumazenil was shown to prevent benzodiazepine sedation if given before the benzodiazepine and to reverse the effect if given during or after the sedative drug. To reverse sedation or general anesthesia of benzodiazepine drugs, flumazenil is administered intravenously in titrated doses from 0.2 to 1.0 mg doses. In the case of overdose, 2.0 to 3.0 mg may be necessary.
Toxicity and safety
"Flumazenil has a high therapeutic index and a wide margin of safety." It showed minimal effect on patients with ischemic heart disease. No withdrawal symptoms were seen when given to patients who had been on diazepam or triazolam for up to 14 days. Some symptoms were seen in patients who had been on loraxepam. It should not be given to patients with severe head injuries and unstable intracranial pressures. When given to patients with panic disorder, 2 mg of flumazenil intravenously precipitated panic attacks. It had no effect on healthy patients.
Use with children
Jones administered flumazenil to 40 healthy children aged 3-12 years of age after they had received 0.5 mg per kg orally for premedication and 0.5 mg per kg intravenously for induction of anesthesia. The drug was given along with a placebo and the efficacy of antagonism was assessed. After surgery they were given 0.1 ml (.001mg. of agent) per kg of solution followed by 0.05 ml. (0.0005 mg of agent) per mg per minute until they were either awake or 10 ml. (1 mg of agent) had been administered intravenously. Each 10 ml. of solution contained 1 mg. of flumazenil. Those receiving the active drug awoke approximately four times faster. The mean total dose of flumazenil administered was 0.024 mg per kg (SD 0.019 mg per kg). There were no cases of resedation and minimal changes in the cardio-respiratory variables.
Use with adults
The half-life of flumazenil at 54 (.7 to 1.3 hr, 50 min. average) minutes is less than midazolam and diazepam so you may see some rebound of effect and may need follow-up doses. Sedation was gone within 2 to 5 minutes. One author saw no improvement after 15 minutes, others showed improvement at 15 and 30 but not 60 minutes. One (1) mg will last for about 2 hours. Flumazenil is rapidly eliminated by the liver. Side effects are infrequent but include mild headache, loss of pupil reactivity to light and mild hypotension.
Contraindications
Flumazenil is contra indicated in patients with a known hypersensitivity to flumazenil or to benzodiazepines, in patients who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g. control of intracranial pressure or status epilepticus), and in patients who are showing signs of serious cyclic antidepressant overdose.
Resedation
Because of the relatively short half life of flumazenil, 0.8 to 1.6 hours, it is possible that its reversal effect could disappear before the sedative effect of triazolam with its half-life 1-2 hours. Midazolam has a similar half-life (1-2 hours) and several studies have failed to show significant resedation if appropriate doses of midazolam had been used. Resedation has been shown with diazepam which has a much longer half-life (20-50 hours) and with larger doses of midazolam. Until studies have been reported showing no resedation with triazolam, a patient who requires flumazenil should be observed for several hours after reversal to be positive resedation does not occur. There is a risk that with reversal the patient may feel normal and attempt activities they are not capable of safely performing.
With the introduction of this reversal agent, we will be able to use triazolam with the comfort of knowing that we should be able to reverse its sedation should we achieve an overdose. Of course, this in no way should cause us to use excessive doses of triazolam, nor does it relieve us of the responsibility of monitoring a patient's physical status and responding accordingly in the case of cardiovascular or respiratory depression.