Antagonizing the errors of history: bedside experience with flumazenil

Figures & data

Figure 1. Clinical use of Flumazenil.

The algorithm summarizes the clinical circumstances and procedure for the use of flumazenil in the emergency department and acute inpatient areas of the study hospital setting.

Figure 2. Retrospective Study Overview.

a) Summarizes the medical toxicology practice cases for the retrospective study, the number treated with flumazenil, the overall response rate, and reported side effects.

b) Reports the number of cases year-by-year over the retrospective study period, and highlights the consistent us of flumazenil each year.

Table 1. Retrospective review of response rates and adverse events with Flumazenil.

		Given Flumazenil				Positive Response
	Total Patients	(N = 519)				(N = 424)
	(N = 5063)	N	%	χ^2	p	N	%	χ^2	p
Gender
Male	2387	219	9.2			179	81.7
Female	2676	300	11.2	5.68	0.017	245	81.7	0.0004	0.984
Past Medical History
Cardiac Disease	307	36	11.7	0.77	0.379	29	80.6	0.03	0.855
Pulmonary Disease	228	48	21.1	30.28	<0.00001	39	81.3	0.01	0.933
Seizure Disorder	221	30	13.6	3.54	0.060	24	80.0	0.06	0.805
Alcohol Abuse or Dependence	1436	258	18.0	129.71	<0.00001	196	76.0	11.25	0.0008
Illicit Substance Abuse or Dependence	947	69	7.3	11.13	0.0009	57	82.6	0.044	0.833
Sedative Abuse	89	71	79.8	475.97	<0.00001	60	84.5	0.44	0.510
Sedative/Hypnotic Dependence*	35	9	25.7	9.16	0.003	8	88.9	0.32	0.574
Present Illness History
Multiple Toxicologic Diagnoses	1873	322	17.2	155.66	<0.00001	258	80	1.40	0.237
Anticholinergic Toxicity	830	67	8.1	5.12	0.024	49	73.1	3.77	0.052
Serotonin Syndrome	699	28	4.0	34.38	<0.00001	26	92.9	2.47	0.116
Stimulant / Sympathomimetic Toxicity	312	11	3.5	16.35	0.00005	10	90.9	0.64	0.425
Sedative / Hypnotic Toxicity	586	436	74.4	2964.47	<0.00001	424	97.2	440.96	<0.00001
Alcohol Intoxication	802	129	16.1	35.25	<0.00001	90	69.8	16.33	0.00005
Anticonvulsant Toxicity	367	140	38.1	334.70	<0.00001	81	57.9	72.86	<0.00001
Antipsychotic / Neuroleptic Toxicity	678	83	12.2	3.37	0.066	56	67.5	13.37	0.0003
Opioid Toxicity	781	134	17.2	47.88	<0.00001	95	70.9	14.09	0.0002
Lithium Toxicity	280	12	4.3	11.46	0.0007	12	100.0	2.75	0.097
Cardiovascular / Antihypertensive Toxicity	246	33	13.4	2.81	0.094	28	84.8	0.23	0.628
Tricyclic Antidepressant Toxicity	311	9	2.9	19.49	0.00001	9	100.0	2.05	0.152

Table 2. Response rates and adverse events with prospective use of Flumazenil.

			Given Flumazenil				Positive Response				Adverse Event
	Total Patients		(N = 212)				(N = 169)				(N = 12)
	(N = 1026)		N	%	χ^2	p	N	%	χ^2	p	N	%	χ^2	p
Gender
Male	493		84	17.0			64	76.2			4	4.8
Female	533		128	24.0	7.60	0.006	105	82.0	1.07	0.301	8	6.3	0.21	0.647
Past Medical History
Cardiac Disease	62		13	21.0	0.004	0.951	12	92.3	1.36	0.244	1	7.7	0.11	0.744
Pulmonary Disease	55		19	34.5	6.83	0.009	16	84.2	0.26	0.610	0	0	1.25	0.263
Seizure Disorder	88		29	33.0	8.87	0.003	15	51.7	16.28	0.00006	0	0	2.02	0.156
Alcohol Abuse or Dependence	275		56	20.4	0.02	0.886	43	76.8	0.40	0.525	3	5.4	0.01	0.909
Illicit Substance Abuse or Dependence	218		32	14.7	6.05	0.014	28	87.5	1.41	0.235	1	3.1	0.45	0.501
Sedative Abuse	103		62	60.2	109.15	<0.00001	52	83.9	0.94	0.334	5	8.1	0.95	0.330
Chronic Sedative Use*	227		102	44.9	104.75	<0.00001	87	85.3	3.78	0.052	8	7.8	1.75	0.185
Present Illness History
Multiple Toxicologic Diagnoses	449		85	18.9	1.46	0.227	64	74.8	1.72	0.190	4	3.5	0.24	0.623
Anticholinergic Toxicity	248		40	16.3	4.10	0.043	34	85.0	0.85	0.356	2	5.0	0.04	0.841
Serotonin Syndrome	160		11	6.9	21.98	<0.00001	10	90.9	14.85	0.0001	0	0.0	0.70	0.404
Stimulant / Sympathomimetic Toxicity	70		6	8.6	6.70	0.010	6	100.0	1.57	0.210	0	0.0	0.37	0.543
Sedative / Hypnotic Toxicity	227		183	80.6	670.48	<0.00001	169	92.3	132.04	<0.00001	11	6.0	0.31	0.579
Alcohol Intoxication	161		41	25.5	2.69	0.101	28	68.3	4.10	0.043	3	7.3	0.26	0.609
Anticonvulsant Toxicity	73		40	54.8	55.85	<0.00001	23	57.5	15.05	0.0001	1	2.5	0.92	0.337
Antipsychotic / Neuroleptic Toxicity	152		17	11.2	9.78	0.002	12	70.6	0.95	0.329	2	11.8	1.29	0.256
Opioid Toxicity	168		49	29.2	8.86	0.003	35	71.4	2.71	0.100	2	4.1	0.30	0.586
Lithium Toxicity	55		7	12.7	2.23	0.135	5	71.4	0.31	0.579	0	0	0.43	0.510
Cardiovascular / Antihypertensive Toxicity	64		16	25.0	0.78	0.376	11	68.8	1.29	0.257	1	6.3	0.01	0.916
Tricyclic Antidepressant Toxicity	72		2	2.8	15.11	0.0001	2	100.0	0.51	0.474	0	0	0.12	0.728
Withdrawal Diagnoses #
Ethanol	53		7	13.2	1.90	0.169	6	85.7	0.16	0.688	0	0	0.43	0.510
Opioids	9		2	22.2	0.01	0.908	2	100.0	0.51	0.474	0	0	0.12	0.728
Sedatives	6		2	33.3	0.59	0.442	2	100.0	0.51	0.474	0	0	0.12	0.728

Table 3. Patients with neurologic and psychiatric comorbidity treated with Flumazenil.

								Side Effects
			Positive Response				Anxiety				Behavioral Disturbance
	(N = 212)		(N = 169)				(N = 7)				(N = 2)
Total Patients Given Flumazenil	N		N	%	χ^2	p	N	%	χ^2	p	N	%	χ^2	p
Neurologic Comorbidity
Seizure Disorder	29		15	51.7	16.28	0.00006	0	0	0.55	0.458	0	0	0.32	0.572
Subtherapeutic AED level	10		7	70.0	0.61	0.434	1	10.0	1.48	0.225	0	0	0.10	0.752
Therapeutic AED level	2		1	50.0	1.10	0.294	0	0	0.07	0.793	0	0	0.02	0.890
Supratherapeutic AED level	15		5	33.3	21.48	<0.00001	0	0	0.55	0.458	0	0	0.15	0.695
Taking Benzodiazepine Only (no other Rx AEDs)	2		2	100.0	0.51	0.474	0	0	0.07	0.793	0	0	0.02	0.890
Traumatic Brain Injury	3		3	100.0	0.77	0.379	0	0	0.10	0.747	0	0	0.03	0.865
Other CNS Disease*	16		11	68.8	1.29	0.257	1	6.3	0.47	0.493	2#	12.5	212.00	<0.00001
Psychiatric Comorbidity
Any Non-Substance-Related Axis I Comorbidity	183		145	79.2	0.19	0.661	7	3.8	1.15	0.284	2	1.1	0.32	0.572
Depressive Disorder	102		83	81.4	0.33	0.564	4	3.9	0.24	0.627	2	2.0	2.18	0.140
Bipolar Disorder	55		44	80.0	0.004	0.952	2	3.6	0.03	0.872	0	0	0.71	0.400
Anxiety Disorder	87		74	85.1	2.60	0.107	6	6.9	5.97	0.015	0	0	1.41	0.236
Chronic Psychotic Disorder	14		10	71.4	0.64	0.425	0	0	0.51	0.474	0	0	0.14	0.706
Attention Deficit Hyperactivity Disorder	32		26	81.3	0.06	0.815	1	3.1	0.004	0.952	0	0	0.36	0.549
Personality Disorder	73		51	69.9	6.69	0.010	3	4.1	0.23	0.633	2	2.7	3.84	0.050

All Chi-square calculations represent comparison of the likelihood of the occurrence (positive response, anxiety or behavioral disturbance) in the group in question to its likelihood in the remainder of the study population.

* Patients cases in this category included diagnoses of brain tumor (1), multiple sclerosis (7), dementia (4), Parkinson's disease (2), and spina bifida (2).

^# Both cases of behavioral disturbance involved the same patient with spina bifida who engaged in self-stimulatory activity after being given antidote during two separate episodes of care. Response to antidote was positive in both instances with wakening from coma.

AED = Anti-epileptic drug, CNS = Central nervous system.

Table 4. Sedating Compounds for which Flumazenil is Antidotal The table lists the intoxicants for which flumazenil was used as antidotal therapy for sedation, coma, and delirium by the medical toxicology service during the seven study years.

Benzodiazepines	Nonbenzodiazepines
Lorazepam	Imidazopyridines
Oxazepam	— Zolpidem
Temazepam	Pyrazolopyrimidines
Clorazepate	— Zaleplon
Alprazolam	Cyclopyrrolones
Clonazepam	— Zopiclone
Diazepam	— Eszopiclone
Triazolam
Estazolam
Midazolam
Chlordiazepoxide
Meprobamate
Flunitrazepam
Muscle Relaxants	Botanicals
Carisoprodol (Meprobamate)*	Uncaria Hook (Uncaria macrophylla)
Metaxalone	Yokukansan (Uncaria rhynchophylla)
Chlorzoxazone
Methocarbamol

* Meprobamate is a metabolite of carisoprodol with benzodiazepine-like GABA-ergic activity.

The parent compound has anticholinergic activity and barbiturate-like GABA-ergic activity.