Revival of an antidote: bedside experience with physostigmine

Figures & data

Figure 1. Clinical use of physostigmine. The algorithm summarizes the clinical circumstances and procedure for the use of physostigmine 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 physostigmine, 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 increasing proportion treated with physostigmine each year.

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

	Total patients		Given physostigmine				Positive response				Adverse event
	(N = 5063)		(N = 868)				(N = 706)				(N = 8)
			N	%	χ^2	p	N	%	χ^2	p	N	%	χ^2	p
Gender
Male	2387		425	17.8			358	84.2			5	1.2
Female	2676		443	16.6	1.39	0.239	348	78.6	4.61	0.032	3	0.7	0.59	0.442
Past medical history
Cardiac disease	307		65	21.2	3.73	0.053	51	78.4	0.38	0.536	2	3.1	3.57	0.059
Pulmonary disease	228		59	25.9	12.80	0.0003	51	86.4	1.09	0.297	0	0	0.59	0.443
Seizure disorder	221		62	28.1	19.36	0.00001	51	82.3	0.04	0.847	0	0	0.62	0.431
Sedative abuse	89		22	24.7	3.66	0.056	15	68.2	2.57	0.109	0	0	0.21	0.647
Alcohol abuse or dependence	1436		230	16.0	1.79	0.181	194	84.3	1.87	0.172	1	0.4	0.81	0.367
Illicit Substance abuse or dependence	947		171	18.1	0.68	0.408	139	81.3	0.0003	0.985	1	0.6	0.27	0.607
Parkinsonism	45		22	48.9	32.21	<0.00001	21	95.5	2.96	0.085	0	0	0.21	0.647
Present illness history
Multiple toxicologic diagnoses	1873		372	19.9	15.45	0.00009	312	83.9	2.75	0.097	4	1.1	0.168	0.682
Anticholinergic toxicity	830		737	88.8	3587.97	<0.00001	706	95.8	672.38	<0.00001	5	0.7	3.16	0.075
Serotonin syndrome	699		242	34.6	174.40	<0.00001	137	56.6	135.10	<0.00001	1	0.4	0.95	0.330
Stimulant/sympathomimetic toxicity	312		94	30.1	39.46	<0.00001	40	42.6	104.45	<0.00001	1	1.1	0.02	0.879
Sedative/hypnotic toxicity	586		87	14.8	2.46	0.117	33	37.9	120.00	<0.00001	0	0	0.90	0.343
Alcohol intoxication	802		125	15.6	1.63	0.202	108	86.4	2.47	0.116	0	0	1.36	0.244
Anticonvulsant toxicity	367		56	15.3	0.99	0.320	34	60.7	16.77	0.00004	0	0	0.56	0.456
Antipsychotic/neuroleptic toxicity	678		283	41.7	333.41	<0.00001	252	89.0	16.44	0.00005	2	0.7	0.21	0.645
Opioid toxicity	781		101	12.9	11.53	0.0007	63	62.4	27.07	<0.00001	1	1.0	0.006	0.939
Lithium toxicity	280		80	28.6	27.25	<0.00001	42	52.5	48.27	<0.00001	1	1.3	0.10	0.747
Cardiovascular/antihypertensive toxicity	246		38	15.4	0.52	0.469	30	78.9	0.15	0.699	0	0	0.37	0.543
TCA toxicity	311		252	81.0	952.04	<0.00001	236	93.7	35.47	<0.00001	0	0	3.30	0.069
	Mean	SD	Mean	SD	OR	95% CI	Mean	SD	OR	95% CI	Mean	SD	OR	95% CI
Age (years)	39.2	15.5	38.4	14.7	0.99874	0.96281–1.03144	38.1	14.3	0.99955	0.96781–1.03696	37.6	12.9	0.98103	0.93512–1.01946

All Chi-square calculations represent comparison of the likelihood of the occurrence (physostigmine given, positive response, or adverse event) in the group in question to its likelihood in the remainder of the study population.

All logistic regression statistics represent the difference in odds (with associated confidence interval) of the occurrence (physostigmine given, positive response, or adverse event) related to an increase of 1 year of age.

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

	Total patients		Given physostigmine				Positive response				Adverse event
	(N = 1026)		(N = 329)				(N = 243)				(N = 24)
			N	%	χ^2	p	N	%	χ^2	p	N	%	χ^2	p
Gender
Male	493		154	31.2			122	79.2			12	7.8
Female	533		175	32.8	0.30	0.584	121	69.1	4.31	0.038	12	6.9	0.11	0.745
Past medical history
Cardiac disease	62		15	24.2	1.88	0.171	11	73.3	0.002	0.962	1	6.7	0.01	0.924
Pulmonary disease	55		19	34.5	0.16	0.686	16	84.2	1.12	0.290	0	0	1.59	0.208
Seizure disorder	88		40	45.5	7.92	0.005	29	72.5	0.04	0.835	1	2.5	1.55	0.213
Sedative abuse	103		38	36.9	1.23	0.269	27	71.1	0.18	0.675	2	5.3	0.26	0.609
Alcohol abuse or dependence	275		78	28.4	2.36	0.124	61	78.2	1.00	0.317	3	3.9	1.80	0.180
Illicit substance abuse or dependence	218		92	42.2	13.05	0.0003	60	65.2	4.94	0.026	9	9.8	1.17	0.280
Parkinsonism	14		11	78.6	14.09	0.0002	10	90.9	1.71	0.191	0	0	0.90	0.344
Present illness history
Multiple toxicologic diagnoses	449		163	36.3	6.58	0.010	122	74.8	0.16	0.687	10	6.1	0.64	0.423
Anticholinergic toxicity	248		245	98.8	668.42	<0.00001	243	99.2	318.73	<0.00001	11	4.5	11.17	0.0008
Serotonin syndrome	160		104	65.0	94.38	<0.00001	49	47.1	56.34	<0.00001	11	10.6	2.42	0.120
Stimulant/sympathomimetic toxicity	70		46	65.7	39.05	<0.00001	18	39.1	33.41	<0.00001	4	8.7	0.16	0.694
Sedative/hypnotic toxicity	227		58	25.5	5.68	0.017	20	34.5	56.55	<0.00001	1	1.7	3.23	0.072
Alcohol intoxication	161		49	30.4	0.23	0.629	35	71.4	0.18	0.675	5	10.2	0.72	0.396
Anticonvulsant toxicity	73		21	28.8	0.39	0.531	13	61.9	1.66	0.198	1	4.8	0.21	0.645
Antipsychotic/neuroleptic toxicity	152		75	49.3	24.45	<0.00001	64	85.3	6.62	0.010	5	6.7	0.06	0.812
Opioid toxicity	168		42	25.0	4.61	0.032	31	73.8	0.0001	0.994	0	0	3.79	0.052
Lithium toxicity	55		23	41.8	2.54	0.111	10	43.5	11.82	0.0006	3	13.0	1.21	0.272
Cardiovascular/antihypertensive toxicity	64		15	23.4	2.33	0.127	8	53.3	3.43	0.064	1	6.7	0.02	0.898
TCA toxicity	72		63	87.5	109.23	<0.00001	62	98.4	24.33	<0.00001	2	3.2	1.96	0.162
	Mean	SD	Mean	SD	OR	95% CI	Mean	SD	OR	95% CI	Mean	SD	OR	95% CI
Age (years)	39.8	13.5	38.5	13.0	0.99275	0.9691–1.05848	38.6	12.9	1.00002	0.98816–1.00824	41.2	15.6	1.01632	0.89544–1.14963

All Chi-square calculations represent comparison of the likelihood of the occurrence (physostigmine given, positive response, or adverse event) in the group in question to its likelihood in the remainder of the study population.

All logistic regression statistics represent the difference in odds (with associated confidence interval) of the occurrence (physostigmine given, positive response, or adverse event) related to an increase of 1 year of age.

Table 3. Electrocardiographic characteristics of patients treated with physostigmine.

Total patients given physostigmine			Positive response				Arrhythmia/cardiac adverse event				Seizure
	(N = 329)		(N = 243)				(N = 1)				(N = 2)
	N	%	N	%	χ^2	p	N	%	χ^2	p	N	%	χ^2	p
Patients with electrocardiography prior to physostigmine	312	94.8	237	76.0			1	0.3			2	0.6
Within 30 minutes of physostigmine	245	74.5	178	72.7			1	0.4			2	0.8
Electrocardiographic characteristics
QRS complex duration (total range 72–168 msec)
72–100 msec	201	64.4	144	71.6	5.77	0.016	1	0.3	0.55	0.457	2	0.6	1.11	0.292
101–130 msec	87	27.9	71	81.6	2.11	0.147	0	0	0.39	0.533	0	0	0.78	0.378
131–160 msec	21	6.7	19	90.5	2.60	0.107	0	0	0.07	0.788	0	0	0.15	0.703
161–168 msec	3	1.0	3	100.0	0.96	0.328	0	0	0.01	0.921	0	0	0.02	0.889
QTc segment duration (total range 341–662 msec)
341–450 msec	79	25.3	53	67.1	4.56	0.033	0	0	0.34	0.560	0	0	0.68	0.409
451–500 msec	160	51.3	132	82.5	7.69	0.006	1	0.3	0.95	0.329	1	0.3	0.00	0.971
501–550 msec	55	17.6	47	85.5	3.30	0.070	0	0	0.22	0.643	1	0.3	1.45	0.228
551–600 msec	13	4.2	8	61.5	1.55	0.214	0	0	0.04	0.835	0	0	0.09	0.767
601–662 msec	5	1.6	3	60.0	0.71	0.400	0	0	0.02	0.898	0	0	0.03	0.856
TCA toxicity (all with <30 min EKGs)	63	19.1	62	98.4	21.79	0.000003	0	0.0	0.25	0.614	0	0	0.51	0.475
			OR	95% CI			OR	95% CI			OR	95% CI
Likelihood of event as function of increasing QRS duration			1.0058	1.00268–1.00973			0.9994	0.99236–1.00501			0.99825	0.89542–1.10097
Likelihood of event as function of increasing QTc duration			1.0009	0.99995–1.00306			0.9996	0.95002–1.04612			1.00075	0.99420–1.00633

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

All logistic regression statistics represent the difference in odds (with associated confidence interval) of the occurrence (positive response, arrhythmia or seizure) related to an increase of 1 msec of EKG measurement.

Table 4. Antimuscarinic compounds for which physostigmine is antidotal.

“Pure” anticholinergics

Atropine

Scopolamine

Hyoscyamine

Cyclic Antidepressants

Doxepin

Amitriptyline

Nortriptyline

Imipramine

Clomipramine

Desipramine

Protriptyline

Amoxapine

Maprotiline

Antihistamines

Hydroxyzine

Diphenhydramine

Doxylamine

Pyrilamine

Chlorpheniramine

Brompheniramine

Clemastine

Antiemetics

Promethazine

Prochlorperazine

Meclizine

Dimenhydrinate

Anti-Parkinson Agents

Benztropine

Trihexyphenidyl

Biperiden

Antipsychotics

Quetiapine

Olanzapine

Clozapine

Loxapine

Chlorpromazine

Fluphenazine

Trifluoperazine

Perphenazine

Thioridazine

Mesoridazine

Thiothixene

Antispasmodics

Dicyclomine

Oxybutynin

Tolterodine

Propantheline

Clidinium

Muscle Relaxants

Baclofen

Carisoprodol

Cyclobenzaprine

Orphenadrine

Glutethimide

Botanicals*

Jimson Weed (Datura stramonium)

Angel’s Trumpet (Brugmansia spp.)

Deadly Nightshade (Atropa belladonna)

Mandrakes (Mandragora officinarum, et al.)

Henbane (Hyoscyamus niger)

Bittersweet (Celastrus scandens)

Lupins (Lupinus spp.)

Fly agaric (Amanita muscaria)

The table lists the intoxicants for which physostigmine was used as antidotal therapy for anticholinergic delirium by the medical toxicology service during the seven study years.

* Potentially beneficial for CNS manifestations of exposure to all plants in the family Solanaceae.