Pediatric poisoning from trimedoxime (TMB4) and atropine automatic injectors

Methods 

Data were collected from two sources: from the Israel Poison Information Center (IPIC) and from patients seen in emergency departments (Eds) in Israel. Calls to the IPIC regarding unintentional injections of AIs during the 1-year period before, during, and after the war in Iraq (August 1, 2002 to July 31, 2003) were prospectively collected. The IPIC is the national poison center of Israel and the only one that serves both the general public and the health system 24 hours a day. Data are recorded on a comprehensive structured form, which includes caller and patient demographic details; route, site, and circumstances of exposure; substance involved; and time elapsed to consultation. It also includes clinical manifestations in a detailed system-oriented approach, management, and follow-up recommendations.

In addition, we conducted a retrospective chart review of children who presented to the EDs of two hospitals in Israel (Assaf Harofeh Medical Center and Ma'aynei-Hayeshua Hospital) during the same period as a result of unintentional injection from an AI that contained atropine and TMB4. Patients seen in these hospitals were not reported to the IPIC.

Assaf Harofeh is a large regional Hospital near Tel Aviv with an active pediatric ED that treats approximately 17,000 patients per year. Ma'aynei-Hayeshua Hospital is a local hospital near Tel Aviv that treats a mainly orthodox Jewish population.

Patients were seen in the ED by the pediatrician on call, and a telephone consult with a toxicologist was offered when needed. Demographic data and data regarding the type of AI, site and time of injection, clinical manifestations, and treatment measures were abstracted from patients records.

The severity of atropinization was based on the score suggested by Amitai et al3 (Table I). Scores of 6 or 7 were considered as normal, 8 to 10 were considered mild, and scores of 11 to 13 were considered severe atropinization. The proportion of symptomatic children, ie, those with an atropinization score of ≥8, was compared using the χ2 test between children injected with an age-appropriate AI and those who received a dose that exceeds the recommended dose. Our institutional review board approved the study.

Table I. Atropinization score (adopted from Amitai et al3)

		Score
	Pupils
	Normal	1
	Dilated	2
	Skin
	Normal	1
	Flushed	2
	Membranes
	Moist	1
	Dry	2
	Temperature °C
	<37.8	1
	>37.8	2
	Neurological state
	Normal	1
	Abnormal (hallucinations, confusion, lethargy, agitation)	2
	Heart rate (beats/min)
	Age <6 HR<140 or age>6 HR<120	1
	Age <6 HR 140-160 or age>6 HR 120-160	2
	Arrhythmia or HR >160 (all ages)	3

HR, heart rate.

Results 

Injection from AI was identified in 148 patients; 122 patients were reported to the IPIC, and 26 were identified at the two hospitals studied (22 patients at Assaf Harofeh and additional 4 patients at Ma'aynei-Hayeshua), of which 25 charts were available for review. Five of the patients reported to the IPIC were excluded because of insufficient data.

Clinical effects 

The observed clinical manifestations are presented in Table II. Local reactions such as severe pain or significant swelling were observed in 37 (26%) cases. At least two signs of atropinization (score 8-10) were found in 42 (30%) of the patients. One patient had signs of severe atropinization (score 11-13). Compared with children injected with an age-appropriate dose, children injected with a dose that exceeds the recommended one were more likely to have an atropinization score ≥8 (9/22 vs 33/104, respectively; P=.029). None of the patients who were asymptomatic on arrival to the ED developed symptoms while in the ED. In 11 patients with electrocardiographic recordings, there were no abnormalities other than sinus tachycardia. Four patients had neurological abnormalities (2 patients with confusion, 1 patient with headache and agitation, and 1 patient with lethargy). There were no side effects characteristic to oximes: no patient demonstrated dizziness, nausea, or muscular weakness.

Table II. Symptoms and signs observed in children after self-injection of atropine and TMB4 AI

	Symptom	No. (%)
	Dilated pupils	38 (26.7)
	Local reactions	37 (26)
	Dry mucus membranes	35 (24.6)
	Tachycardia	32 (22.5)
	Flushed skin	21 (14.8)
	Abnormal neurological state	4 (2.8)
	Other∗	5 (3.5)

∗ Includes 2 patients with vomiting, 1 patient with headache and sore throat, 1 patient with fever, and 1 patient with abdominal pain.

Discussion 

We report unintentional pediatric exposure to atropine and TMB4; in the 142 cases reported, there were no serious adverse events. All the patients, except one, were treated as outpatients or were discharged home from the ED.

Oximes are compounds that contain the radical R2C=N.OH derived from condensation of aldehydes or ketones with hydroxylamine. In organophosphate poisoning, oximes are used because of their ability to reactivate acetylcholinesterase at nicotinic receptors and, to a lesser degree, at muscarinic sites.4., 5. Other effects of oximes are inhibition of Na+ conductance, inhibition of various synaptic receptors, and reversible inhibition of acetylcholinesterase.6 Members of the oxime group include pralidoxime, obidoxime, the H oximes HI-6 and Hlo-7, methoxime, and TMB4.

With some organophosphate nerve agents, the binding of the warfare agent to acetylcholinesterase becomes irreversible (ageing) within a few minutes. If oximes were given after the “ageing process” had occurred, they would not be effective. Incorporating an oxime into an AI will increase the likelihood of reactivating acetylcholinesterase.

The only oxime approved by the Food and Drug Administration for use in the United States is pralidoxime. The methanesulfonate salt of pralidoxime (P2S) is the standard oxime in the United Kingdom. Obidoxime (toxogonin) is used in Israel and in some European countries. In Israel, TMB4 is not in routine use for cases of organophosphate intoxication, but it has been incorporated into the AI found in personal chemical warfare defense kits. TMB4 is very stable in injectable solutions7 and is therefore suitable for AI. Studies in animals8., 9., 10. and clinical experience in humans11., 12. demonstrated that adding oximes to atropine may improve the outcome of poisoning from acetylcholinesterase inhibitors. Oximes may have different efficacy after intoxications from different organophosphates.13., 14.

Adverse effects of oximes are rarely reported.15., 16. Dizziness or blurred vision and increased diastolic blood pressure were reported after rapid infusion of pralidoxime.15 Obidoxime has been reported to be associated with pallor, nausea, headache, generalized weakness, sore throat, and paresthesia of the face muscles.17 Arrhythmias and liver dysfunction were described in patients who received high doses of obidoxime and atropine.18 It has been suggested, however, that the liver dysfunction in these cases is because of organophosphate intoxication not because of the treatment with obidoxime.19

Compared with atropine alone, adding TMB4 to atropine increased survival rates in mice exposed to physostigmine.9 The LD50 for TMB4 in the presence of atropine, however, was much lower than the LD50 of TMB4 alone, suggesting that the combination of atropine and TMB4 is more toxic. Data on adverse effects of TMB4 in humans are limited. Described adverse effects include heavy headedness, tension headache, facial flushing, dry mouth, and numbness in the face and limbs.20 These adverse effects, which are in part similar to the effect of atropine, occurred when 150 mg of TMB4 was given intravenously. Because of these effects and despite being more effective than other oximes such as pralidoxime and pyridine-aldoxime-methylchloride in cases of organophosphate poisoning, some advocate not using TMB4 for routine treatment.20

Our findings do not support these opinions. None of the children who accidentally received an AI that contained atropine and TMB4 developed severe adverse reaction. Even in the 22 case patients who received a higher dose there were no serious adverse effects.

The current report also demonstrates the effects of mass distribution of AIs to the general population. Henretig et al21 demonstrated that it is possible to discharge an AI containing atropine and pralidoxime into a small, sterile vial. The vial contents could than be used for intramuscular injection of these antidotes to small children on a milligram per kilogram basis. This approach might be considered when AI-containing pediatric doses are not available.

The current study has some limitations. In some cases we could not determine the exact dose injected by the AI. Because data were reported to the IPIC from many sources and because some of the data were collected retrospectively not all patients underwent a standard evaluation. The reports may have been affected by different interpretations by physicians. The treatment also was not standardized, as is reflected by the fact that all 4 patients in one of the hospitals were treated with intravenous fluids, whereas none of the 22 patients in the other hospital required fluid therapy. The IPIC management recommendations do not include routine intravenous fluids but rather oral hydration, as needed. The relatively small size of the series does not allow us to draw a definite conclusion about the outcome of combined TMB4 and atropine injection in children.