Review articleShould a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department?☆,☆☆
Introduction
Patients in coma with suspected drug poisoning are seen commonly in the emergency department (ED). They constitute a high-risk group1 that are resource demanding and require urgent management and diagnostic procedures.2
In cases of self-induced poisoning, the drugs ingested frequently involve multiple medications and their identity is often unknown.3 The benzodiazepines are the most commonly used drugs in self-poisoning, and have been reported to involve about half of all drug poisoning in several countries.2, 4, 5 Drug induced coma may be associated with significant morbidity, such as aspiration pneumonia, pressure syndromes, rhabdomyolysis and cerebral hypoxia.
An agent that reverses coma or reduces its severity may have a place in the ED. Flumazenil is an imidazole-benzodiazepine that blocks the central effects of benzodiazepine.6 This antagonist has a high affinity for the benzodiazepine receptors in the brain and acts as a strong competitive antagonist. An immediate response to flumazenil can confirm the diagnosis of benzodiazepine poisoning7, 8 and can make it possible to interview the patient for a more complete history of drugs taken. This may render resource-demanding diagnostic interventions and management (e.g. orotracheal intubation) unnecessary9, 10 and may reduce operational costs in the ED and contact time with the patient.
However, flumazenil can cause significant complications such as seizures, particularly in patients who have ingested heterocyclic antidepressants or are chronic benzodiazepine users who may be otherwise stable at presentation.11, 12, 15 It may also cause intractable myocardial dysrhythmias (especially in patients with co-ingestion of alcohol and/or heterocyclic antidepressants) and even death,13, 14, 15, 16 usually as a result of the reversal of the depressant effect of benzodiazepines on the sympathetic nervous system. Other minor side effects may include shivering, nausea, vomiting, anxiety, restlessness and vomiting17 and aspiration in patients who may are obtunded.
Flumazenil may also induce benzodiazepine withdrawal syndrome, especially in chronic users of benzodiazepines. Flumazenil has a half-life of less than an hour, hence resedation may occur. Moreover, benzodiazepine intoxication is generally well tolerated even in large doses, so the use of flumazenil has been questioned.18, 19
Some physicians have suggested that flumazenil be used as a therapeutic and diagnostic tool7, 8, 20 in cases of suspected poisoning presenting with somnolence or depressed consciousness.9, 13
In this systematic review, we examine the effectiveness of giving flumazenil in patients with coma from suspected drug poisoning and to assess the associated major and minor outcomes encountered. No known meta-analysis of this literature has been published to date.
Section snippets
Objectives
The objective of this review was to determine the effectiveness and safety of flumazenil in people with coma from suspected drug overdose.
Criteria for considering studies for review
Type of participants: Studies including adults or children presenting to the ED or intensive care unit with decreased level of consciousness attributable to poisoning by unknown agents including benzodiazepines.
Type of intervention: Flumazenil (intravenous bolus administration of any dosage) compared to placebo.
Types of outcome measures: The primary outcome sought was improvement in the level of consciousness within 5 min of giving the drug. This should be defined by coma scoring systems such as
Search strategy
We conducted a literature search using MEDLINE from 1966 to December 2005, EMBASE from 1974 to December 2005 and the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2005. We used the search terms coma [MeSH], flumazenil or anexate (free text search), and overdose or poisoning (free text search). The search was limited to randomised controlled trials (RCTs) and there was no language restriction. Reference list of all studies and review articles were reviewed to identify
Methods of the review
Retrieval of studies were performed by two reviewers (AN, CR), who reviewed the literature searches independently to identify potentially relevant trials for full review. Searches of bibliographies and texts were conducted to identify additional studies. From the full text, using specific criteria, two reviewers independently selected trials for inclusion (EW, RP). Disagreement was resolved by consensus or third party adjudication (AN) (Figure 1).
Statistical analysis
For binary (dichotomous) data, a pooled relative risk (with 95% confidence intervals) was calculated using a fixed effects model. Potential result heterogeneity between studies was assessed by visually examining the forest plots and by using the I2 statistic21. If there was significant heterogeneity between studies a random effects model was used to calculate the overall pooled estimate. An I2 value greater than 50% was considered as substantial heterogeneity and the sources for heterogeneity
Study description and validity
All seven trials which met our inclusion criteria10, 17, 22, 23, 24, 25, 26 were published in English and they were conducted in Canada, Sweden, Switzerland, United States, Israel and Australia. All were single centre studies except Spivey et al.,26 which was a multi-centre trial. The 7 trials had a sample size ranging from 32 to 170 patients and were justified by stating the expected treatment effect, power and significance level explicitly.
The studies were conducted either in the ED or in an
Methodological qualities of included studies
All studies were double-blinded, placebo controlled and randomised with similar patient baseline characteristics. Only one study25 detailed the method of concealment of allocation and method of randomisation with all the withdrawals accounted for. One study22 had no mention of method of randomisation, concealment of allocation, blinding method or intention to treat analysis. The other studies had mention of intention to treat analysis and withdrawals, but no details of the concealment of
Study selection
The electronic search identified 113 studies, of which 20 studies were RCTs that were published between 1987 and 2005. Independent review of the abstracts and titles identified 13 potentially relevant studies. Additional references were sought from a bibliographic search of relevant articles, but no additional articles were found. A total of 13 trials were reviewed for inclusion. Independent review of these potentially relevant articles resulted in seven studies meeting the inclusion criteria
Effect of flumazenil versus placebo
The main results were either reported as a dichotomous outcome (woke up from coma) or as a continuous outcome (GCS score of patients). Secondary outcomes reported were the major and minor side effects encountered. Six studies10, 17, 22, 24, 25, 26 had relevant data and the overall pooled estimate shows that the relative benefit of waking up from consciousness was significant in patients treated with flumazenil compared to the placebo group (Relative benefit 4.99, 95% CI 3.14–7.92) Figure 2.
Discussion
Patients in coma with suspected drug poisoning are commonly encountered in the ED. Benzodiazepines are one of the most commonly used drugs in self-poisoning.4, 5
The pooled results appeared to show that flumazenil was more effective than placebo in terms of awakening from coma within 5–15 min. The relative benefit of patients who awoke from coma was 4.99 (95% CI 3.14, 7.92) and the relative benefit in GCS score was 1.12 (95% CI 0.69, 1.56). Both were statistically significant.
The risk of having a
Conclusion
This meta-analysis shows that flumazenil may be effective in the reversal of coma in patients with drug poisoning although the clinical significance of benefit is difficult to determine. Current evidence may not be sufficient to support the routine use of flumazenil in the emergency department. A clinical approach may be employed in the emergency department as a diagnostic and therapeutic ‘trial’ in patients with coma from suspected drug poisoning. Relative contraindications should include
Conflict of interest
There is no funding or outside support, information or financial interest in the product studied or the company that produces it.
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2015, NeuroToxicologyCitation Excerpt :Another well-known medicine that exerts its effect via the GABAA-R is flumazenil. It reverses the potentiation of the GABA response that benzodiazepines induce through binding at the benzodiazepine binding site of the GABAA-R. Therefore, it is used as an antidote/diagnostic tool in benzodiazepine intoxications (Ngo et al., 2007). Since GABAA-R antagonists reduce inhibitory GABAergic input on e.g., catecholaminergic neurons, a subsequent increase in catecholamine release can occur (McKernan and Whiting, 1996; Kiyatkin and Rebec, 1998; D’Hulst et al., 2009).
Neurotoxic Emergencies
2013, Psychiatric Clinics of North AmericaCitation Excerpt :Flumazenil binds to the benzodiazepine site on the GABA receptor, competitively inhibiting benzodiazepines and related xenobiotics. Although flumazenil effectively reverses the CNS effects of these agents,84 it is not recommended for routine use on all altered or comatose patients because of the potential for inducing withdrawal in the chronic user, provoking seizures in both epileptic and nonepileptic patients, and unmasking excitatory coingestants. Reasonable use of flumazenil would be in benzodiazepine overdose in naïve patients and iatrogenic benzodiazepine overdose from procedural sedation.85
A poison center's ten-year experience with flumazenil administration to acutely poisoned adults
2012, Journal of Emergency MedicineCitation Excerpt :In all these studies, no seizures occurred. Furthermore, a meta-analysis from 2007 that included 466 patients reported that flumazenil effectively reversed coma among overdose patients with an overall seizure frequency of 0.2% (10). Contrary to these reports, other authors have cautioned against the use of flumazenil in unknown overdose patients, due to the risk of precipitating seizures.
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A Spanish translated version of the summary of this article appears as Appendix in the final online version at 10.1016/j.resuscitation.2006.11.010.
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This paper was presented as a poster at the ACEP 2005 in Washington.