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Neonicotinoids are a new class of insecticides widely applied for crop protection. These insecticides act as agonists at nicotinic acetylcholine receptors, which cause insect paralysis and death. The high specificity for receptors in insects was considered to possess highly selective toxicity to insects and relative sparing of mammals. However, an increasing number of cases of acute neonicotinoid poisoning have been reported in recent years. We reported a man who developed respiratory failure and shock after ingestion of neonicotinoid insecticide. A detailed literature review found that respiratory, cardiovascular and certain neurological presentations are warning signs of severe neonicotinoid intoxication. The amounts of ingested neonicotinoid insecticide and the plasma neonicotinoid concentration are not useful guides for the management of intoxicated patients. Supportive treatment and decontamination are the practical methods for the management of all neonicotinoid-poisoned patients.
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There are currently seven members in the class of neonicotinoid insecticides: imidacloprid, acetamiprid, clothianidin, thiacloprid, dinotefuran, nitenpyram and thiamethoxam. (The structures of these different neonicotinoids are listed in fig. 1). Therefore, a literature search was performed with the following keywords: ‘poisoning’, ‘intoxication’, ‘neonicotinoid’, ‘imidacloprid’, ‘acetamiprid’, ‘clothianidin’, ‘thiacloprid’, ‘dinotefuran’, ‘nitenpyram’ and ‘thiamethoxam’ from 1960 to the present. The researched databases included PubMed and Google Scholar, and the articles were cross-referenced with the initial studies.
The clinical outcomes, as modified from the American Association of Poison Control Center data collection system, were classified as non-severe and severe . The poisoned patients who exhibited signs or symptoms that were life-threatening or resulted in significant disability or disfigurement (e.g. status epilepticus, respiratory failure, ventricular tachycardia with hypotension, cardiac or respiratory arrest, disseminated intravascular coagulation, massive haematemesis or melena) were categorized as severe. Other clinical presentations were categorized as non-severe. We used Fisher's exact test to analyse the dichotomous variables of the collected data.
Two original articles and 12 case reports about toxidromes of neonicotinoid intoxication in human beings were reviewed [4-14, 16-18]. Besides, we added our case for data analysis. A total of 152 cases were included in the reviewed articles, being 22 severe cases and 130 non-severe cases. Twenty-one (16%) severe cases and 110 (84%) non-severe cases were poisoned by oral ingestion. Only 1 (5%) severe case and 20 (95%) non-severe cases were poisoned via inhalation and dermal contact. When comparing the route of ingestion and the routes of inhalation and dermal contact, we found no difference in the severity of intoxication (p = 0.31). The study population and route of neonicotinoid poisoning are illustrated in fig. 2. Imidacloprid was the major poison in these patients, which constituted 94% of the intoxication events. Acetamiprid and clothianidin accounted for 5% and 1% of the remaining poisonings, respectively (fig. 3). Because imidacloprid is the first commercialized neonicotinoid insecticide and the best selling insecticide in the world, we concluded that the wide use of imidacloprid was the reason why most patients were intoxicated with this neonicotinoid insecticide . Four of the reviewed cases died, and the estimated mortality was 2.6% (4/152). Most patients underwent supportive management including decontamination, symptomatic treatment, airway protection and respiratory and haemodynamic support. Atropine and pralidoxime were used in 5 patients and 1 patient, respectively, and the effects of the two medications were inconclusive.
Figure 2. The study population and routes of neonicotinoid poisoning. *One non-severe case was poisoned via both ingestion and subcutaneous injection.
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Figure 3. Imidacloprid constituted 94% of the neonicotinoid insecticide intoxication events. The remaining 6% of poisonings resulted from acetamiprid (5%) and clothianidin (1%), respectively.
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A study by Phau et al.  included 70 cases, but only 50 cases with detailed records of clinical presentations were evaluated. Another study conducted in Sri Lanka included 68 patients, but the symptoms were described for only two severe cases . In addition, we noted the clinical features in 14 of the intoxicated cases presented in the 12 case reports as well as the present case. In sum, the clinical details of 66 intoxicated patients with 22 severe cases and 44 non-severe cases were recorded. Age, sex, type of neonicotinoid, prognosis, poisoning effect and clinical presentations of these patients are presented in table 1. The average age of the severe group was higher than that of the non-severe group (58 versus 49 years old, p < 0.05).
Table 1. A summary of the literature review, including important clinical details regarding age, sex, type of neonicotinoid, prognosis, poisoning outcome and clinical presentations
|Authors||Age||Sex||Type of neonicotinoid||Intentional/Accidental contact||Co-exposure substances||Route of exposure||Prognosis||Poisoning outcome||Clinical presentations|
|Wu et al. ||64||M||Imidacloprid||Intentional||Nil||Ingestion||Alive||Non-severe||Vomiting, diaphoresis, dizziness, fever, oral ulcer, dysphagia, abdominal pain|
|Huang et al. ||69||F||Imidacloprid||Intentional||Nil||Ingestion||Expire||Severe||Apnoea, coma, ventricular tachycardia, hypotension, vomiting, diaphoresis, oral ulcer|
|David et al. ||22||M||Imidacloprid||Intentional||Nil||Ingestion||Alive||Non-severe||Tachycardia, vomiting, bradycardia, fever|
|Agarwal et al. ||24||M||Imidacloprid||Accidental||Nil||Inhalation and dermal contact||Alive||Severe||Dyspnoea, coma, tachycardia, diaphoresis, fever|
|Shadnia et al. ||35||M||Imidacloprid||Intentional||Nil||Ingestion||Expire||Severe||Apnoea, coma, tachycardia, hypotension, nilbradycardia, dizziness, vomiting, mydriasis, fever|
|Todani et al. ||79||M||Acetamiprid||Intentional||Nil||Ingestion||Alive||Severe||Coma, tachycardia, hypotension, vomiting|
|Panigrahi et al. ||37||M||Imidacloprid||Intentional||Nil||Ingestion||Alive||Severe||Dyspnoea, coma, tachycardia, mydriasis|
|Karatas et al. ||67||M||Imidacloprid||Intentional||Nil||Ingestion||Alive||Severe||Apnoea, coma, tachycardia, hypotension, mydriasis|
|Imamura et al. ||58||M||Acetamiprid||Intentional||Nil||Subcutaneous injection & ingestion||Alive||Non-severe||Vomiting, seizure|
|74||M||Acetamiprid||Intentional||Nil||Ingestion||Alive||Severe||Tachycardia, hypotension, vomiting, seizure|
|Chwaluk et al. ||48||F||Imidacloprid||Accidental||Nil||Inhalation and dermal contact||Alive||Non-severe||Vomiting|
|Iyyadurai et al. ||34||M||Imidacloprid||Intentional||Nil||Ingestion||Expire||Severe||Apnoea, coma, hypotension, diaphoresis, bradycardia, mydriasis|
|Yeh et al. ||67||M||Imidacloprid||Intentional||Alcohol||Ingestion||Expire||Severe||Apnoea, coma, ventricular tachycardia, hypotension, bradycardia|
|Lin et al. ||56||M||Imidacloprid||Intentional||Alcohol||Ingestion||Alive||Severe||Dyspnoea, coma, tachycardia, hypotension, vomiting, diaphoresis, oral ulcer, fever|
|Mohamed et al. ||35||F||Imidacloprid||Intentional||Nil||Ingestion||Alive||Severe||Apnoea, coma, tachycardia, hypotension,|
|26||M||Imidacloprid||Intentional||Alcohol||Ingestion||Alive||Severe||Coma, vomiting, mydriasis|
|Phua et al. ||10 severe and 40 non-severe cases|
We selected 14 common presentations observed in at least 5% of the patients in a single group and compared the incidences of these presentations between the severe and non-severe groups. The results are shown in fig. 4. We found that the severe group had higher rates of dyspnoea/apnoea, coma (Glasgow Coma Scale < 8), tachycardia, hypotension, mydriasis and bradycardia (73% versus 2%, 64% versus 2%, 50% versus 5%, 45% versus 0%, 23% versus 0%, 18% versus 2%, respectively, p < 0.05).
The number of cases of neonicotinoid poisoning appears to have increased from 2007 to 2011. Only 2 cases were reported from 2001 to 2006, whereas 11 case reports involving 12 cases were reported from 2007 to 2011. This finding is in line with the article of Phau et al.  who reported 14 neonicotinoid exposures from 1993 through 2002 that were followed by a dramatic increase to 56 cases between 2003 and 2007. The most likely explanation for this trend is the wide application of neonicotinoid insecticides in recent years. In addition, the presence of neonicotinoid-poisoned patients has alerted physicians to other possible cases.
Neonicotinoid acts on nicotinic acetylcholine receptors in the nervous system. It initially stimulates the agonized receptors and interferes with the transmission of neuronal impulses by fatigue [20, 21]. The effect influences the central nervous system and results in dizziness, drowsiness, disorientation and coma. The autonomic nervous system is stimulated through a similar mechanism, first with diaphoresis, mydriasis, tachycardia and elevations of blood pressure. The stimulation may lead to coronary spasm and cardiac ischaemia, followed by nervous system paralysis. As a result, poisoned patients may present with arrhythmia, hypotension and bradycardia.
The solvents used in neonicotinoid insecticides may also play a role in the toxidromes of neonicotinoid poisoning. Although we do not know the solvents included in all neonicotinoid insecticides worldwide, many neonicotinoid insecticides use N-methyl pyrrolidone (NMP) as the solvent in Taiwan and Sri Lanka (the cases from the two countries constitute 93% of all reviewed cases) [4-6, 14, 16]. A large amount of NMP ingestion irritates the upper gastrointestinal tract and results in oral ulcers, nausea, vomiting, dysphagia, odynophagia and abdominal pain . In addition, airborne exposure to NMP induces central nervous system depression in rats, which may worsen the neurological symptoms of neonicotinoid intoxication .
In neonicotinoid-intoxicated patients, neurological depression decreases airway protection, and cardiac depression further aggravates the load of respiration. Furthermore, corrosive injury to the upper gastrointestinal tract induces mucosal oedema of the airway, and the resultant inflammatory process precipitates fever and hypotension . The combination of aspiration due to the lack of airway protection, airway obstruction due to corrosive injury to the airway mucosa and increased respiratory load due to inflammation and shock contributes to the evolution of respiratory failure.
Several mechanisms participate in the development of toxidromes in neonicotinoid-poisoned patients, and the clinical features therefore varied between reports. Accordingly, physicians need to know the warning signs of severe neonicotinoid intoxication. We found that gastrointestinal symptoms and minor neurological presentations occurred equally in both the severe and non-severe groups. Conversely, respiratory, cardiovascular and some neurological symptoms (coma and mydriasis) occurred more commonly in severely intoxicated patients. Meticulous observation is indicated in neonicotinoid-poisoned patients presenting with these warning signs.
The more severe cases had a greater tendency to result from oral ingestion than inhalation or dermal contact. However, the difference in the incidence of severe intoxication between the two routes of exposure is insignificant. Phau et al.  found that the amounts of ingestion in severe poisoning cases were less than the amount in non-severe cases. The study from Sri Lanka discovered that the plasma concentrations of neonicotinoid insecticide were high and remained elevated up to 10–15 hr after ingestion in many intoxicated patients; however, only two patients developed severe symptoms . A report of two fatalities due to neonicotinoid intoxication in Portugal measured the post-mortem plasma concentrations, which were not greater than the median level demonstrated in the study from Sri Lanka . These facts revealed that the plasma concentration does not appear to be useful for guiding clinical management. The presence of severe respiratory, cardiovascular and neurological symptoms is a practical guide for treating patients with neonicotinoid poisoning.
Calumpang and Medina reported that adequate protective equipment, including hat, goggles, gloves, apron and boots, can markedly reduce exposure to neonicotinoid insecticides during spraying . All poisoning patients should undergo skin decontamination and remove the contaminated clothes because neonicotinoid insecticides could be absorbed by inhalation and dermal contact. Gastrointestinal decontamination can be conducted by the insertion of a gastric tube and stomach content withdrawal. Gastric lavage and activated charcoal should be avoided whenever corrosive injuries to the oral and gastrointestinal mucosa are discovered. The severity of poisoning is not proportional to the plasma neonicotinoid concentration. Therefore, there is currently no role for haemoperfusion to increase neonicotinoid elimination. Supportive management is adequate for all neonicotinoid-poisoned patients.
With the wide application of neonicotinoid insecticides, the numbers of neonicotinoid poisonings have increased in the last decade. Respiratory, cardiovascular and certain neurological presentations (dyspnoea/apnoea, coma, tachycardia, hypotension, mydriasis and bradycardia) are warning signs of severe neonicotinoid intoxication. The amounts of ingested neonicotinoid insecticide and the plasma neonicotinoid concentration are not useful guides for the management of intoxicated patients. Supportive treatment and decontamination are the current practical management methods for all neonicotinoid-poisoned patients.