Elsevier

Resuscitation

Volume 74, Issue 1, July 2007, Pages 27-37
Resuscitation

Review article
Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department?,☆☆

https://doi.org/10.1016/j.resuscitation.2006.11.010Get rights and content

Summary

Patients in coma with suspected drug poisoning are commonly encountered in the emergency department. Benzodiazepines are one of the most commonly used drugs in self-poisoning. Flumazenil, a benzodiazepine antagonist has been suggested as a diagnostic and treatment tool in suspected poisoning of unclear cause, but caution is required due to potential side effects. No systemic review of this literature has been done on this topic.

Objectives

The aim of this study is to examine if flumazenil should be used in patients with coma from suspected drug poisoning.

Search strategy

Randomised controlled trials were identified from the Cochrane Library, Pubmed and EMBASE. Bibliographies from included studies, known reviews and texts were searched. Content experts were contacted.

Selection criteria

Randomised controlled trials were eligible for inclusion. Studies were included if patients who presented with altered mental state from suspected drug poisoning were treated with intravenous flumazenil as compared to placebo.

Data collection and analysis

Data were extracted and methodological quality was assessed independently by two reviewers.

Main results

Seven randomised controlled trials were included. A total of 466 patients were involved.

Flumazenil was found to reverse coma from suspected drug poisoning with a relative benefit of 4.45 (95% CI 2.65, 7.45). In terms of major side effects, there was no statistical difference between flumazenil and placebo (RR 2.86, 95% CI 0.12–69.32). However, in terms of minor side effects, flumazenil was associated with a higher incidence of anxiety (RR 2.84, 95% CI 1.28–6.30) and other side effects (RR 3.73, 95% CI 2.078–6.73). There was no difference in the incidence of vomiting (RR 4.28, 95% CI 0.95–19.35).

Conclusion

Current evidence shows that flumazenil may be effective in the reversal of coma in patients presenting to the emergency department with coma from suspected drug poisoning.

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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    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.

    ☆☆

    This paper was presented as a poster at the ACEP 2005 in Washington.

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