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Flumazenil Not Living Up to the Hype

Roberts, James R. MD

doi: 10.1097/01.EEM.0000482472.97837.98
InFocus

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, CEN, athttp://emn.online/ProceduralPauseEMN, and read his past columns athttp://emn.online/InFocusEMN.

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Flumazenil, when it was first introduced more than 25 years ago, promised to be an effective and safe antidote for any patient who might have benzodiazepine (BZD) toxicity. It was hyped to be like naloxone, a complete and excellent reversal agent with no downsides, even if BZDs were not contributing to the overdose. Flumazenil is a complete antidote in that it will immediately reverse all BZD effects, but its empiric use has not gained wide popularity for a number of reasons.

This antidote essentially has minimal upsides and some substantial downsides. Individuals who are truly BZD-addicted can suffer immediate BZD withdrawal from flumazenil use. BZD withdrawal is not usually life-threatening, but it can be associated with undesirable side effects and rarely seizures. Flumazenil can cause seizures in patients who have ingested seizurogenic drugs, the poster child being tricyclic antidepressants, so the universal empiric use of flumazenil as part of the so-called coma cocktail has been discouraged. BZD intoxication is generally well tolerated, even in large doses, but it can cause prolonged coma and respiratory depression, particularly when mixed with other sedative hypnotics and alcohol. Still, the empiric use of flumazenil in unknown overdoses and comatose patients has limited applicability.

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Lack of Adverse Effects of Flumazenil Administration: An ED Observational Study

NguyenTT, TroendleM, et al.

Am J Emerg Med

2015:33(11):1677

This is a recent review of 23 patients who received flumazenil in the ED for suspected BZD toxicity. The study sought to assess adverse events and clinical outcomes of flumazenil administration in the ED in known and suspected BZD overdose. The authors note that flumazenil has a high affinity for BZD-binding sites on the GABA receptor. It acts as a competitive antagonist at this receptor and reverses all of the sedative and respiratory depressant effects of all BZDs. The authors' review of the flumazenil literature found that seizures associated with this drug were generally related to patients who had received BZDs for a seizure, in those with a BZD overdose combined with a pro-convulsive drug, andor in patients with chronic BZD dependence.

This retrospective study required six years in an urban tertiary Level I trauma center to find only 23 patients with complete data. The investigators collated the type of overdose, the mental status before and after flumazenil, vital signs, and the presence of seizures following use of the antidote. Their data included only adults, who had a mean age of 43. About half of the overdoses were iatrogenic. The antidote was given intravenously in all cases at a starting dose of 0.2 mg regardless of the acuity of the ingestion or clinical status. The final mean dose was 0.35 mg. Eight of the 23 individuals had a pro-convulsive co-ingestion, usually cocaine, but bupropion, diphenhydramine, and methamphetamine were also reported. No seizures were documented. About 60 percent of the patients experienced some type of mental status improvement.

Overall, flumazenil was safe, and no significant changes in vital signs were seen after the administration. Flumazenil has been suggested as an alternative to intubation, but this study could not identify those who received flumazenil for that purpose. Interestingly, 11 of the 23 patients never had a BZD screen performed. This is a small study, but no seizures were reported in the 30 percent of patients who were theoretically at risk because of concomitant effects of pro-convulsive medication. The authors concluded that additional studies on the use of flumazenil for suspected BZD toxicity were warranted.

Comment: Flumazenil administration in the ED has a theoretical role as a diagnostic and therapeutic tool. But it is not used very much in the ED despite its potential benefits. Its use in serious polydrug overdoses is somewhat unclear, and many clinicians are hesitant to administer it except under pristine circumstances. The use deemed safest is for reversal of iatrogenic overdose from excessive BZD sedation provided by the clinician.

These authors note that the national poison data system reported in 2013 that flumazenil was given only 1,688 times, less often than fomepizole. The majority of patients had improved mental status after flumazenil administration and no seizures were found, and the authors concluded that additional studies are warranted to clarify the role of flumazenil in the ED for suspected BZD toxicity. I truly doubt if more study is required. Simply stated, potential adverse effects are not worth the risks in the poorly characterized overdose (as most are in the ED), although flumazenil does work.

It is interesting to speculate that the concomitant deliberate ingestion of BZDs may actually be clinically helpful in patients who overdose on seizurogenic or neurotoxic substances, further questioning the need for routine BZD reversal even if present. This review does indicate, however, that concomitant ingestion of seizurogenic drugs does not always mean a flumazenil-induced seizure will occur.

It would seem most reasonable to use flumazenil in a pediatric patient who overdosed on an adult's BZD or in patients who are given too many BZDs for conscious sedation. These are relatively clean cases that should have little or no chance for adverse reactions. The initial 0.2 mg recommended dose may not be enough for complete reversal of a large BZD overdose. Spivey, et al., found that up to 3 mg were required in some cases. (Ann Emerg Med 1993;22[12]:1813.) I doubt if any emergency clinician uses such doses these days.

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Empiric Use of Flumazenil in Comatose Patients: Limited Applicability of Criteria to Define Low Risk

Gueye PN, Hoffman JR, et al.

Ann Emerg Med

1996;27(6):730

This is a retrospective review of 35 consecutive comatose patients who were given flumazenil for presumed significant drug overdose. The authors attempted to determine if simple clinical rules could differentiate between high- and low-risk patients, and identify those in whom flumazenil could be effective and safe.

Patients were categorized on initial clinical presentation into a flumazenil low-risk and a non-low-risk group. Low-risk criteria included a clinical picture compatible with uncomplicated BZD intoxication, the absence of findings suggestive of a stimulant or antidepressant overdose, and the absence of an available history of an underlying seizure disorder or long-term BZD use. The initial presentation was considered an uncomplicated BZD intoxication if the patient were described as calm and had no localizing neurological signs, hypertonia, myoclonus, hyperreflexia, documented abnormalities in heart rate, widened QRS complex, or an obvious anticholinergic or sympathomimetic syndrome. All others were placed in the non-low-risk subgroup. Overall, only four of 35 patients met the criteria that clinically described an uncomplicated BZD overdose.

Most of the study patients were given flumazenil in the prehospital phase, specifically in a mobile unit staffed by a physician. The mean loading dose of flumazenil was 0.5 mg. A continuous infusion was initiated when the patient had a complete response. All patients in the group considered low-risk had some awakening following flumazenil administration. Only four of 31 patients in the non-low-risk group had complete awakening, and 71 percent had no response.

Most (87%) of the non-low-risk subgroup were intubated. No seizures were reported in the patients with low-risk criteria, but five of 31 patients in the non-low-risk group did demonstrate seizure activity within 60 minutes of flumazenil use. All patients with seizures had neurological or ECG abnormalities that would generally contraindicate the use of flumazenil because the clinical criteria ruled out a straightforward uncomplicated BZD overdose. These patients were quite ill, and three in the non-low-risk group died. The exact contribution of flumazenil to an adverse outcome was not known.

These authors concluded that patients identified as low risk may safely receive flumazenil, but a low-risk label applies to only a small portion of comatose patients with suspected drug overdose. Comatose patients with clinical or ECG criteria thought to contraindicate the use of flumazenil have a high risk of seizures after administration of the drug. The criteria to define low risk, therefore, had limited applicability in real life.

Comment: It is unclear if flumazenil actually caused significant harm in any patient, but this article should give one caution against the routine use of flumazenil as a diagnostic or therapeutic tool in undifferentiated overdose, especially in obviously sick patients. The sagacious ED clinician may be able to characterize patients at low risk from flumazenil, but a careful and complete evaluation is required. A low-risk patient is basically sleeping, with normal vital signs, a normal ECG, and a benign neurologic exam except for coma. There is no tachycardia, hyperreflexia, or myoclonus. Precipitating a seizure in the critically ill overdose patient can cause significant effects, even death. The acidosis produced by a seizure in a TCA overdose patient, for example, can double the amount of free tricyclic antidepressant in the serum and can be rapidly lethal. Two patients in this study had multiple seizures.

A significant TCA overdose is less common these days, and significant TCA toxicity should not be a subtle presentation. Ferreting out such patients requires a careful and complete evaluation prior to flumazenil intervention. Patients with low-risk criteria would likely be few and far between in most EDs because serious suicide attempts usually involve more than simple BZD ingestion. These authors concluded that flumazenil should not be given empirically to all patients with coma, and such intervention is potentially dangerous in patients who do not meet low-risk criteria. The number of patients in this low-risk category is likely to be minimal.

Overall, the clinical utility of routine empiric flumazenil for the unknown overdose remains quite limited. The emergency clinician should probably forget about the reflexive use of flumazenil in almost all unknown drug overdoses. A severe pure BZD ingestion is unlikely. In fact, there may be significant benefits to the BZD component in those who have polydrug ingestion, particularly when a pro-convulsive medication is also ingested. It would be most prudent to consider diagnostic or therapeutic flumazenil use in the pediatric patient who is very symptomatic, likely from an isolated BZD overdose, but even these patients should be carefully evaluated for the presence of neurologic toxicity from another ingestion. Probably the safest use of flumazenil in the ED is to reverse excessive sedation from BZDs used for painful procedures.

The initial hope that flumazenil would be part of the coma cocktail has not been realized, and its use in the ED will likely be quite limited. The only real adverse effect of excessive BZDs is respiratory depression, and it just might be safer to intubate and mechanically ventilate the patient rather than chance the adverse effects from flumazenil unless there is excellent confirmation of a simple BZD overdose in a non-BZD chronic user. Finding BZDs on the drug screen does not change this recommendation.

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