A22: Antidotes in Depth

Flumazenil is a competitive benzodiazepine receptor antagonist. Its role in patients with an unknown overdose is limited because seizures and dysrhythmias may develop when the effects of a benzodiazepine are reversed if the patient has taken a mixed overdose. Flumazenil also has the potential to induce benzodiazepine withdrawal symptoms, including seizures in patients who are benzodiazepine dependent. Flumazenil does not reliably reverse the respiratory depression induced by intravenous (IV) benzodiazepines.²¹ Flumazenil is the ideal antidote for the relatively few patients who are both naïve to benzodiazepines and who overdose solely on a benzodiazepine as well as benzodiazepine-naïve patients whose benzodiazepine component must be reversed after procedural sedation. Because the duration of effect of flumazenil is shorter than that of most benzodiazepines, repeat doses may be necessary and vigilance is warranted. Flumazenil has no role in the management of ethanol intoxication. Flumazenil may be considered for patients with hepatic encephalopathy although further study is necessary before it can be recommended.⁴ Case reports raise the possibility of a role for flumazenil in patients with paradoxical reactions to therapeutic doses of benzodiazepines.⁷¹ Flumazenil was not effective in overdose of baclofen in which a benzodiazepine receptor is not involved.¹⁵ Flumazenil is effective for overdoses of zolpidem and zaleplon, nonbenzodiazepines that interact with ω₁ receptors, a subclass of central benzodiazepine receptors.^43,53,56

The initial work of Haefely and Hunkeler⁶⁷ on chlordiazepoxide synthesis led to an attempt to develop benzodiazepine derivatives that would act as antagonists.³³ This endeavor was initially unsuccessful but led to the promising γ-aminobutyric acid (GABA) hypothesis as the benzodiazepine mechanism of action. In 1977 radioligand binding identified specific high-affinity benzodiazepine binding sites. Other investigators simultaneously isolated a product produced by a Streptomyces species that had the basic 1,4-benzodiazepine structure. Synthetic derivatives of this molecule led to the creation of benzodiazepines with potent anxiolytic and anticonvulsant activity and diminished sedative and muscle-relaxing properties. Testing revealed these derivatives had high in vitro binding affinities, but lacked in vivo activity. An inability to enter the central nervous system (CNS) was considered an explanation for the discordance. During an experiment that attempted to demonstrate CNS penetration of these derivatives, diazepam given to incapacitate the animals had a surprisingly weak effect. This lack of potency led to the discovery of a benzodiazepine antagonist. Further modifications led to the synthesis of flumazenil (Ro 15-1788).^20,57

Mechanism of Action

The benzodiazepine receptor modulates the effect of GABA on the GABA_A receptor by increasing the frequency of Cl^– channel opening, leading to hyperpolarization. Agonists such as diazepam stimulate the benzodiazepine receptor to produce anxiolytic, anticonvulsant, sedative-hypnotic, amnestic, and muscle relaxant effects. Flumazenil is a water-soluble benzodiazepine analog with a molecular weight of 303 Da. It is a competitive antagonist at the benzodiazepine receptor, with very weak agonist properties both in animal models and in humans.⁵² Inverse agonists bind the benzodiazepine receptor and result in the opposite effects of anxiety, agitation, and seizures. Antagonists, such as flumazenil, competitively occupy the benzodiazepine receptor without causing any functional change and without allowing an agonist or inverse agonist access to the receptor. The zero set point of intrinsic activity may be influenced by the activity of the GABA system or by chronic treatment with benzodiazepines.²⁴ Positron emission tomography investigations reveal that 1.5 mg of flumazenil leads to an initial receptor occupancy of 55%, whereas 15 mg causes almost total blockade of benzodiazepine receptor sites.⁶⁰

Table A22–1 summarizes the physiochemical and pharmacologic properties of flumazenil.^21,37 Volunteer studies demonstrate that the ability of flumazenil to reverse the effects of sedating doses of IV benzodiazepines (eg, 30 mg diazepam, 3 mg lorazepam, 10 mg midazolam) is dose dependent and begins within minutes.¹⁸ Peak effects occur within 6 to 10 minutes.²¹ Most individuals achieve complete reversal of benzodiazepine effect with a total IV dose of 1 mg, titrated in 0.2 mg aliquots.^5,14 A 3 mg IV dose produces similar effects that last approximately twice as long as the 1 mg dose.

A number of studies evaluated patients who received midazolam or diazepam (average doses of 10 and 30 mg, respectively) as conscious sedation for endoscopy or cardioversion.^{6,13,14,17,39,40} When a benzodiazepine is given for conscious sedation during a procedure, flumazenil appears safe and effective for reversal of sedation and partial reversal of amnesia and cognitive impairment.²⁷ Most patients respond to total doses of 0.4 to 1 mg.²¹ Administering flumazenil slowly at a rate of 0.1 mg/min minimizes the disconcerting symptoms associated with rapid arousal, such as confusion, agitation, and emotional lability. Residual sedation becomes evident within 20 to 120 minutes, depending on the dose and pharmacokinetics of the specific agonist benzodiazepine and the dose of flumazenil.²⁷ For this reason, patients must be carefully monitored and subsequent doses of flumazenil titrated to clinical response. Because the amnestic effect of benzodiazepines and the cognitive and psychomotor effects are not fully reversed, posttreatment instructions should be reinforced in writing and given to a responsible caregiver accompanying the patient.^18,27 Because of the risk of resedation, health care professionals infrequently elect to use flumazenil.

Two patients undergoing endoscopy who developed seizures following benzodiazepine reversal are reported.⁶⁴ One patient had a history of seizures, and the other had no obvious etiology. Both patients recovered uneventfully.

Paradoxical reactions to benzodiazepines are unpredictable and documented in as many as 1% to 10% of adults and in 3.4% of children.^30,48,49 Common features include worsening restlessness, agitation, disorientation, flailing, and dysphoria.^26,28,54,71 The mechanism is unclear and has been attributed to a disinhibition reaction.²³ These reactions are reported to occur from several minutes to 210 minutes after initiation of sedation.^28,71 Management strategies include administering higher doses of the benzodiazepines, adding other drugs such as opioids or droperidol, stopping the procedure, and using flumazenil.^26,49,54,71 IV flumazenil was administered to six adults with paradoxical reactions to midazolam in 0.1 mg aliquots. Doses of 0.2 to 0.5 mg were effective in all the patients with a response occurring within 30 seconds.⁷¹ Attention to other causes of unexpected behavior such as hypoxia or hypoglycemia must be addressed and corrected.

Although the flumazenil package insert carries an indication for the management of benzodiazepine overdose, the role of flumazenil in the overdose setting is controversial.^41,68 The first argument against flumazenil use is the rare morbidity and mortality associated with benzodiazepine use. An analysis of 702 patients who had taken benzodiazepines alone or in combination with ethanol or other drugs and were subsequently admitted to a medical intensive care unit over a 14-year period revealed a 0.7% fatality rate (five deaths) and 9.8% complication rate (69 patients).³⁶ In comparison, the fatality rate for patients with nonbenzodiazepine related overdoses was 1.6% (55 of 3430 patients). In the pure benzodiazepine group, two patients died and 18 (12.5%) of 144 patients had complications, mostly aspiration pneumonitis and decubitus ulcers. Proponents of flumazenil therapy suggest that some of the 29 diagnostic procedures used in the patients were unnecessary, and some of the complications could have been prevented by the use of flumazenil. Others suggest that many of the cases of aspiration pneumonitis occurred prior to hospital admission and that the patients also suffered from trauma and infectious diseases, making most diagnostic procedures necessary.

In an effort to develop indications for safe and effective use of flumazenil, overdosed comatose patients were retrospectively assigned to either a low-risk or non–low-risk group.³¹ Low-risk patients had CNS depression with normal vital signs, no other neurologic findings, no evidence of ingestion of a tricyclic antidepressant by history or electrocardiography, no seizure history, and absence of an available history of chronic benzodiazepine use. All other patients fell into the non–low-risk category. Of 35 consecutive comatose patients, 4 were assigned to the low-risk group. Flumazenil resulted in complete awakening in three patients and partial awakening in the fourth patient in the low-risk group, with no adverse events. In the non–low-risk group of 31 patients, flumazenil caused complete awakening in four patients and partial awakening in five patients. Seizures occurred in five patients, of whom only one had a history of seizures, five were long-term benzodiazepine users, four had abnormal vital signs prior to reversal, and three had evidence of hyperreflexia or myoclonus. Therefore, although flumazenil use probably was safe and effective in the low-risk group, few patients could be considered low risk. The risk of seizures appears substantial in non–low-risk patients.

The risks of flumazenil usually outweigh the benefits in patients with overdoses.⁶¹ When non–benzodiazepine-dependent patients ingest benzodiazepines alone in overdose, as rarely occurs in adults but might be expected in children, the risks associated with flumazenil are limited.^41,73Table A22–2 summarizes the indications for flumazenil use in the overdose setting.

Hepatic Encephalopathy

Hepatic encephalopathy is considered a reversible metabolic encephalopathy characterized by a spectrum of CNS effects. Symptoms may progress from confusion and somnolence to coma. One current hypothesis implicates an increase in GABAergic tone in the development of encephalopathy.^7,63

Animal studies of hepatic encephalopathy secondary to galactosamine or thioacetamide (hepatotoxins) demonstrate an increase in GABA effect, which is antagonized by flumazenil, bicuculline (a GABA receptor antagonist), and isopropylbiclophosphate chloride (a calcium channel blocker).⁷ Cerebrospinal fluid (CSF) from these animals contained a benzodiazepine receptor ligand with agonist activity. Rat studies involving hepatic encephalopathy resulting from acute liver ischemia showed only a slight response to flumazenil, but significant improvement after administration of a partial inverse agonist.^12,69

Human studies have detected benzodiazepine binding activity in the CSF (but not in serum) of patients with hepatic encephalopathy. One group identified four to 19 peaks representing benzodiazepine binding ligands from the frontal cortex of 11 patients who died of hepatic encephalopathy.¹⁰ Two of the peaks were further characterized as diazepam and N-desmethyldiazepam. Brain concentrations of these substances were 2 to 10 times higher than normal in six of the patients and were normal in five patients. Patients with idiopathic recurring stupor who have measurable “endozepines” (endogenous benzodiazepine ligands) in serum and CSF are reported.^58,66

Flumazenil improves the clinical and electrophysiologic responses of patients with hepatic encephalopathy and idiopathic recurring stupor.^4,8,19,58,66 Some patients with encephalopathy have improved from stage IV to stage II encephalopathy following IV flumazenil. Maximal improvement after flumazenil lasts approximately 1 to 2 hours and gradually dissipates within 6 hours. The response rate in a meta-analysis averaged approximately 30%.²⁹ The proposed explanations for the unresponsiveness include cerebral edema, hypoxia, other systemic diseases or complications, and irreversible CNS damage.

Animal and human data convincingly support the concept that increased GABAergic tone is responsible for hepatic encephalopathy. Evidence for endogenous benzodiazepine ligands that enhance GABA action also are demonstrated but controversial.^1,3 The source of these benzodiazepine receptor agonists is unclear, but diet and/or production by gut bacteria is postulated.⁷ Most authorities believe endogenous de novo synthesis is unlikely and propose prior benzodiazepine exposure and persistence of clinical effects as an explanation. Hyperammonemia, neurosteroids, and hemoglobin metabolites are also implicated in the pathophysiology of hepatic encephalopathy.^3,11,59

Flumazenil can lead to short term improvement of the clinical condition of a subgroup of patients with hepatic encephalopathy and may prove useful as an addition to conventional therapy.^2,4,9 Existing guidelines recommend use be reserved for patients with acute hepatic encephalopathy and a history of benzodiazepine use.^11,22 Additional research is necessary to prospectively identify responders, provide dosing considerations, and evaluate adverse events. There is no known survival benefit.

Ethanol Intoxication

Animal studies indicate that many of the actions of ethanol are mediated through GABA neurotransmission.⁶⁵ Acute ethanol administration appears to enhance GABA transmission and inhibit N-methyl-d-aspartate excitation. Chronic ethanol administration leads to downregulation of the GABA system. Ethanol enhances GABA_A induced chloride influx in a dose-dependent fashion without a direct effect on chloride. Flumazenil does not influence this action of GABA. Chronic ethanol use selectively increases the sensitivity to inverse benzodiazepine agonists, invoking a change in coupling or conformation of the receptor. These changes may explain the development of tolerance and the kindling and production of seizures that occur on ethanol withdrawal.

A randomized, double-blind, crossover study of eight male volunteers given IV ethanol to achieve a constant serum ethanol concentration of 160 mg/dL was conducted.¹⁶ Once stabilized, the volunteers were given either placebo or 5 mg flumazenil. Subjective and objective psychomotor tests were conducted, with no differences noted between volunteers given flumazenil and volunteers given placebo. Thus the probability of ethanol reversal at the doses achieved appears unlikely.

Based on this information, flumazenil likely does not have a significant effect on ethanol intoxication, and low doses of flumazenil (< 1 mg) have no effect.^44,47 The 5 mg doses reportedly produce favorable changes in sensorium, but these findings may be the result of confounding factors. Because we would not administer 5 mg flumazenil in the overdose setting to avoid the increased risk of adverse effects at this dose, flumazenil cannot be recommended for reversal of ethanol intoxication.

Flumazenil has been studied in more than 3500 patients worldwide, including healthy volunteers and overdosed patients, or patients who had undergone conscious sedation. The safety of flumazenil in healthy volunteers is well established, with no discernible objective or subjective effects. However, seizures in benzodiazepine-dependent patients, dysrhythmias in patients who coingest a benzodiazepine and a prodysrhythmic xenobiotic, and resedation within 20 to 120 minutes in patients receiving benzodiazepines for conscious sedation are recognized adverse events associated with flumazenil administration.

The ability of flumazenil to precipitate acute benzodiazepine withdrawal seizures in a more controlled environment than the overdose setting was demonstrated by reversal of long-term benzodiazepine sedation in the intensive care unit. A study of 1700 patients revealed that 14 patients developed adverse drug reactions—probably one-half of these reactions were related to abrupt arousal.⁶ Two patients with a history of epilepsy developed tonic–clonic seizures, and one patient developed myoclonic seizures.⁶ Dose-dependent induction of withdrawal reactions is therefore suggested. Small total doses (< 1 mg) of titrated flumazenil may allow sufficient occupation of the benzodiazepine receptor sites by benzodiazepines to limit the occurrence of withdrawal seizures.

In a study of 12 patients receiving midazolam sedation for 4 ± 3 days, 0.5 mg flumazenil was administered as a rapid bolus. Serum norepinephrine and epinephrine concentrations rose within 10 minutes, returned to baseline within 30 minutes, and correlated with increased heart rate, blood pressure, and myocardial oxygen consumption.³⁸

Flumazenil causes a significant overshoot in cerebral blood flow and may cause a large increase in intracranial pressure in patients who receive midazolam for severe head injury.⁷⁵

Thirty published case studies involving 758 patients with drug overdoses were reviewed.²⁵ In total, 387 patients participated in double-blind study protocols and 371 patients in open-label studies.²⁵ Fifty percent of cases were of mixed overdoses. The doses of flumazenil ranged from 0.2 to 5 mg. Five cases of seizures were temporally related to flumazenil administration, all after large bolus doses. In three of the five patients, high concentrations of tricyclic antidepressants were present in the blood. The seizures resolved either without treatment or following administration of a small dose of a benzodiazepine. Dysrhythmias developed in two patients given small doses of flumazenil, both presumably associated with the presence of a tricyclic antidepressant. Of 497 patients enrolled in two clinical US studies sponsored by the manufacturer,²⁵ six patients developed seizures (five had coingested tricyclic antidepressants) and one patient who had taken a tricyclic antidepressant and carbamazepine had a junctional tachycardia, which normalized after several minutes. Thus, in reviewing 1255 patients, 11 patients had seizures and three developed dysrhythmias, for an incidence of approximately 0.9%. The consensus report was that (a) flumazenil is not a substitute for primary emergency care, (b) hypoxia and hypotension should be corrected before flumazenil is used, (c) when used, small titrated doses of flumazenil should be given, (d) flumazenil should not be used in patients with a history of seizures, evidence of seizures or jerking movements, or evidence of a tricyclic antidepressant overdose, and (e) flumazenil should not be used by inexperienced clinicians.

An analysis of all seizures associated with flumazenil gathered from previously published cases or reports to the manufacturer was published.⁶⁴ Forty-three patients had seizures and six patients died, but the author believed that none of the deaths were attributable to flumazenil.⁶⁴ Four patients developed status epilepticus; two were presumed to be caused by concomitant tricyclic antidepressant exposure, and the other two patients had received benzodiazepines to treat status epilepticus prior to flumazenil therapy. In six of 43 seizure episodes, the relationship to flumazenil use was believed to be inadequately defined. The remaining 37 patients were stratified into five categories. In category 1, seven patients were given flumazenil after they had received a benzodiazepine for treatment of a seizure disorder. Six of these seven patients received greater than 1 mg flumazenil. In category 2, 20 patients received flumazenil for reversal of a benzodiazepine in a mixed-drug overdose. Many of these patients had coingested tricyclic antidepressants. Thirteen of these patients received more than 1 mg flumazenil. Two of the patients in this group developed status epilepticus and died, possibly secondary to a severe tricyclic antidepressant overdose. Category 3 included five patients who received benzodiazepines for suppression of non–drug-induced seizures. Two of these five patients received more than 1 mg flumazenil. Category 4 included three patients with acute benzodiazepine overdoses in the presence of chronic benzodiazepine dependence. Category 5 included two patients who received a benzodiazepine for conscious sedation. Therefore, flumazenil use may place the patient at risk for seizures by unmasking a toxic effect in mixed overdose, by removing the protective anticonvulsant effect in a patient with non–drug induced seizures, or by precipitating acute benzodiazepine withdrawal. Table A22–3 summarizes the contraindications and precautions to flumazenil use.

Flumazenil has not consistently reversed benzodiazepine induced respiratory depression and is not suggested as the initial intervention should respiratory depression occur.^21,46,50,62 It is likely that following oral overdose, benzodiazepine-induced respiratory insufficiency is related to smooth muscle relaxation resulting in a mechanical effect with an increase in upper airway resistance and obstructive apnea rather than a central effect.³² Although flumazenil might improve the clinical situation,^32,55 other standard procedures such as airway repositioning, supplemental oxygen, bag-valve-mask ventilation, and endotracheal intubation, if indicated, should be used either prior to or during reversal.

Flumazenil is US Food and Drug Administration (FDA) pregnancy category C. There are no adequate studies done in pregnant women.²¹ It is not known whether flumazenil is excreted in breast milk.²¹

Slow IV titration (0.1 mg/min), and waiting one minute between doses, to a total dose no higher than 1 mg seems most reasonable. Administration into a large freely running vein minimizes the potential for pain at the injection site. Resedation may occur at 20 to 120 minutes, and readministration of flumazenil may be necessary. Although not approved by the FDA, continuous IV infusion of flumazenil 0.1 to 1.0 mg/h in 0.9% sodium chloride solution or 5% dextrose in water has been used following the loading dose.^43,72,74

Flumazenil is available by many manufacturers in a concentration of 0.1 mg/mL with parabens in 5 and 10 mL vials.

• The risks of flumazenil appear to greatly outweigh the potential benefits of reversal when benzodiazepines are used chronically or acutely to treat a seizure disorder.

• Flumazenil is best avoided in the overdose setting when evidence indicates coingestion of a drug capable of causing seizures or dysrhythmias.

• Flumazenil should also not be used when involvement of a tricyclic antidepressant is strongly suggested based on history, clinical findings, or findings on electrocardiography (prolonged QRS complex).^35,45,51,70

• Any indication that theophylline, carbamazepine, chloral hydrate, chloroquine, and or chlorinated hydrocarbons was ingested is a contraindication to flumazenil use.⁷⁰

• In the event of flumazenil induced seizure, a therapeutic dose of a benzodiazepine such as diazepam or lorazepam should be effective; however, due to the competitive nature of flumazenil, higher doses will be necessary to reverse higher doses of flumazenil.

References