Anesth Analg 2006;103:410-412
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000222470.89210.5a
CRITICAL CARE AND TRAUMA
A Mixture of Organophosphate and Pyrethroid Intoxication Requiring Intensive Care Unit Admission: A Diagnostic Dilemma and Therapeutic Approach
Mukesh Tripathi, MD, MNAMS,
Rajesh Pandey, MD, PDCC,
Sushil P. Ambesh, MD, and
Mamta Pandey, MBBS, PGDHHM
From the *Department of Anesthesiology and Critical Care, BP Koirala Institute of Health Sciences, Dharan, Nepal; 
Department of Anesthesiology and 
Emergency Department, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Address correspondence and reprint requests to Mukesh Tripathi, MD, MNA, MS, Type IV-21, Campus, SGPGIMS, Lucknow-226014, India. Address e-mail to mukesh_tripathi{at}yahoo.com.
 |
Abstract
|
|---|
The illegal mixing of organophosphates and pyrethroids in marketed agriculture insecticides is becoming prevalent in developing countries. Over a 12-mo period, 8 patients were admitted to the emergency department of a university hospital in Dharan, Nepal after ingestion of such a mixture with suicidal intent. All patients presented with a combination of miosis, bradycardia, tachypnea, and unconsciousness. The occurrence of both pupillary dilation after a small-dose infusion of atropine (0.08 to 0.2 mg/kg in 1–3 h) and seizures raised the possibility of pyrethroid poisoning. In each case, an examination of the insecticide container confirmed that it contained a mixture of organophosphate and pyrethroid. After seizure control, gastric lavage, respiratory support, hemodynamic stabilization and diuresis, seven of the patients recovered without neurological deficit. One patient suffered aspiration pneumonia and died. The early clinical picture after this mixed poisoning is based on the toxicity of organophosphates rather than pyrethroids. Because the patients responded to a small dose of atropine with mydriasis and tachycardia, it suggested a mixed poisoning. Early suspicion of mixed poisoning may have a significant prognostic impact.
|
Introduction
|
|---|
The commonly used household products and pesticides reported in accidental and nonaccidental poisoning include organochlorines, organophosphates, carbamates, pyrethroids, nitrophenols and chlorophenols (1). Although the large majority of all pesticides are used in the developed world, 99% of all acute pesticide poisoning occurs in developing countries. Attempted suicide accounts for two thirds of all pesticide poisoning fatalities (1). Pyrethrum and synthetic pyrethrin derivatives are used in many household and agricultural insecticides and are variously presented as powders, sprays, mosquito coils, and solutions for wood treatment.
Generally, pyrethroids are considered safe for human use because of their selective toxicity to the insect nervous system, relatively low toxicity for mammals, poor dermal absorption, and rapid metabolism with little tissue accumulation. Fatal pyrethroid poisoning reports are not common in the toxicology literature. Only a few severe systemic life-threatening pyrethroid-induced illnesses have been reported in developing countries (2–5). However, the trend toward increased marketing of unauthorized pyrethroid-organophosphate mixtures is likely to result in an increase in the prevalence of mixed toxicity (2). Here, we present eight cases of acute systemic pyrethroid poisoning resulting in a combination of coma, seizure, and pulmonary edema.
|
CASE SERIES
|
|---|
Over a 12-mo period, 8 adult patients (5 females and 3 males aged 34 to 62 yr) were brought to the emergency department of a university hospital in Dharan, Nepal, for treatment of suspected ingestion of insecticide with suicidal intent. All were unconscious and had poorly reacting pinpoint pupils, increased salivation, and rapid, shallow tachypnea (respiratory rate >30/min). Organophosphate poisoning was suspected, and treatment was started immediately according to our institutional protocol. This included gastric lavage with normal saline and activated charcoal, IV atropine by infusion (20–25µg/min) and pralidoxime (1 g every 6 h). All 8 patients developed generalized convulsions 4 to 12 h after ingestion while receiving oxygen by mask. Six patients had abnormal choreoathetosis movement of the limbs preceding the seizure and coma. The pupillary dilation after only a very small dose of atropine (0.08 to 0.2 mg/kg over 1 to 3 h) was remarkable (Table 1).
On further investigation and an examination of the poison container, it became apparent that the ingestate contained a pyrethroid (lambda-cyhalothrin) and an organophosphate (methyl-parathion) in a ratio of 4:1. Approximately 1 h after ingestion, and before complete loss of consciousness, 5 of the patients had complained of epigastric pain, nausea, and vomiting.
Atropine and pralidoxime treatment was stopped. Seizure frequency, which was 10-15 per day during the first 2 days, decreased significantly on the third day. Seizure control was achieved with a bolus of midazolam (0.1 mg/kg) followed by an infusion titrated to effect (0.1–0.5 mg · kg–1 · h–1) and IV sodium hydantoin (100 mg over 30 min once per day).
The patients also suffered severe pulmonary edema (presence of bilateral crepitations on auscultation and chest radiograph and pink frothy secretions through the endotracheal tube). While in the intensive care unit, all patients required tracheal intubation and mechanical ventilation with varied levels of positive end-expiratory pressure to maintain arterial Pao2 (>95 mm Hg) and Paco2 (35 to 40 mm Hg). A forced diuresis with mannitol (1 g/kg) and furosemide (20 mg) and other support measures (mechanical ventilation, antibiotics, midazolam infusion, acid prophylaxis, and nasogastric feeding) continued. The patients regained consciousness after 24 to 48 h and were weaned from mechanical ventilation in 2 to 3 days. Seven patients made a complete recovery with no neurological deficit. One patient died from a severe aspiration syndrome caused by vomiting during transfer to the hospital.
|
DISCUSSION
|
|---|
These eight patients were diagnosed and treated for acute organophosphate poisoning (the most common insecticide intoxicant in this region) on the basis of clinical presentation in the emergency department. However, the occurrence of sensitivity to atropine, seizures, and pulmonary edema suggested the possibility of poisoning by other agents. This was confirmed by examination of the poison container. The seven survivors regained consciousness after seizure control and mechanical ventilation.
Pyrethrins are active extracts derived from Chrysanthemum cinerariifolium. There are more than 1000 pyrethroids, which are the synthetic analogs of these natural products, and pyrethrum was the first identified. Pyrethrum is regarded as the safest of the insecticides because of its high selectivity and toxicity for the insect nervous system and minimal dermal absorption (6).
In an extensive review of 573 cases of acute pyrethroid poisoning between 1983 and 1988 in China, most occurred from either occupational or accidental exposure (4). A severe form of accidental pyrethroid poisoning was reported after inadvertent introduction of the insecticide into air-conditioning ducts; those exposed suffered dyspnea, nausea, headache, and irritability (3). In a series of five cases of suicidal pyrethroid poisoning reported in India, vomiting was present in four patients, drowsiness in three, excessive salivation and convulsions in one each, and hypernatremia in two (5). Chronic sequelae to pyrethroid exposure include cerebro-organic disorders, sensomotor-polyneuropathy involving the lower extremities, and vegetative nervous disorders, such as paroxysmal tachycardia, increased heat sensitivity, and reduced exercise tolerance related to circulatory dysfunction (7).
The principal signs of pyrethroid toxicity result from excitatory neurotoxicity. On the basis of chemical structure and the presence of tremor or choreoathetosis with salivation, the effects of pyrethroids have been classified as Type I and II syndromes. Type I syndrome presents as a reflex hyperexcitability and fine tremor. The clinical picture of Type II syndrome is of choreoathetosis, salivation, seizures, and potent sympathetic activation (8). Simple skin contamination alone may result in paresthesia (9). Pyrethroid-induced disruption of voltage-sensitive sodium channel function keeps these channels open for prolonged periods, resulting in hyperexcitation of the entire nervous system (10–12). These agents also block the 
-amino-butyric-acid chloride receptor channel complexes, but the mechanism is less well understood (12,13). An in vitro study has shown that the calcium channel blockade may cause some of the chronic effects of low-level pyrethroid poisoning (14). However, existing data neither support nor conclusively refute the hypothesis that its effects on voltage-sensitive calcium channel are important in acute pyrethroid-induced neurotoxicity (15). The effects of pyrethroids on peripheral-type benzodiazepine receptors are unlikely to be a peripheral cause of pyrethroid intoxication, but they may contribute to or enhance convulsions caused by pyrethroids' action on other target sites (8).
In severe cases, organophosphate poisoning (e.g., paraoxon, soman, and sarin) are reported to induce seizures or status epilepticus (16). This is associated with damage to the hippocampal area of the brain, which has extensive cholinergic innervation (17). These seizures are resistant to conventional antiepileptics, such as phenytoin and carbamazepine (18). A study on a guinea pig hippocampal slice demonstrated the ability of anticholinergics and benzodiazepines to inhibit organophosphate-induced epileptiform activity (19).
In our cases, the occurrence of complete neurological recovery and the reversal of both miosis and bradycardia by the administration of a relatively small dose of atropine conflicted with the diagnosis of severe organophosphate poisoning. Given that the seizures started when the patients were well oxygenated, either by facemask or through ventilatory support, hypoxia was unlikely to have been the cause of seizure in these patients. In addition, severe pulmonary edema is not usually reported with organophosphate poisoning. In our series of cases, the pulmonary edema may have been related to the pyrethroid-induced neuroexcitation and sympathetic surge (release of norepinephrine) (20). Mechanical ventilation, with moderate positive end-expiratory pressure, and forced diuresis improved pulmonary edema.
As illegal mixing of compounds in insecticides is becoming more prevalent, more cases of mixed poisoning will occur (2). He et al. (21) have shown that a 2-hour exposure to organophosphates, alone or in combination with pyrethroids, will inhibit acetylcholine esterase to a similar extent. Because organophosphates are more potent than pyrethroids, our patients showed clinical features of organophosphate poisoning up to the point of the occurrence of choreoathetoid movement preceding convulsions and the signs of atropinization with small doses of atropine. Seven of our patients regained consciousness after only 24 hours of seizure control, mechanical ventilation, and supportive therapy. This further demonstrates the relative safety margin, and moderate neurotoxic manifestations generally resolved spontaneously (22).
In summary, mixing of pesticides not only compromises the safety of marketed insecticides or pesticides but may also pose a clinical diagnostic dilemma. As the clinical presentation may be confusing, this series of cases emphasizes the importance of retaining and examining the poison container. The presentation of seizure disorder and pulmonary edema in a suspected case of pure organophosphate poisoning should raise the suspicion of the presence of other agents. Undue sensitivity to a very small dose of atropine should increase this level of suspicion.
|
ACKNOWLEDGMENTS
|
|---|
The authors thank Dr. Eamon McCoy, Consultant Anesthesiologist, The Royal Victoria Hospital, Belfast, for his critical reading and editing of the manuscript.
|
Footnotes
|
|---|
Accepted for publication March 28, 2006.
|
REFERENCES
|
|---|
- Koh D, Jeyaratnam J. Pesticides hazards in developing countries. Sci Total Environ 1996;188:S78–85.
- Ray DE, Forshaw PJ. Pyrethroid insecticides: poisoning syndromes, synergies, and therapy. J Toxicol Clin Toxicol 2000;38:95–101.[ISI][Medline]
- Chen SY, Zhang ZW, He FS, et al. An epidemiological study on occupational acute pyrethroid poisoning in cotton farmers. Br J Ind Med 1991;48:77–81.[ISI][Medline]
- He F, Wang S, Liu L, et al. Clinical manifestations and diagnosis of acute pyrethroid poisoning. Arch Toxicol 1989;63:54–8.[ISI][Medline]
- Peter JV, Cherian AM. Pyrethroid poisoning. J Assoc Physicians India 1996;44:343–4.[Medline]
- Williams RL, Bernaud CE, Krieger RI. Human exposure to indoor residential cyfluthrin residues during a structured activity program. J Expo Anal Environ Epidemiol 2003;13:112–9.[ISI][Medline]
- Muller-Mohnssen H. Chronic sequelae and irreversible injuries following acute pyrethroid intoxication. Toxicol Lett 1999;107:161–76.[ISI][Medline]
- Soderlund DM, Clark JM, Sheets LP, et al. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology 2002;171:3–59.[ISI][Medline]
- Knox JM, Tucker SB, Flannigan SA. Paresthesia from cutaneous exposure to a synthetic pyrethroid insecticide. Arch Dermatol 1984;120:744–6.[Abstract]
- Miyamoto J, Kaneko H, Tsuji R, Okuno Y. Pyrethroids, nerve poisons: how their risks to human health should be assessed. Toxicology 1995;82/83:933–40.
- Costa LG. Basic toxicology of pesticides. Occup Med 1997;12:251–68.[Medline]
- Narahashi T. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology 1996;78:1–14.
- Forshaw PJ, Lister T, Ray DE. The role of voltage-gated chloride channels in type II pyrethroid insecticide poisoning. Toxicol Appl Pharmacol 2000;163:1–8.[ISI][Medline]
- Hildebrand ME, McRoy JE, Snutch TP, Stea A. Mammalian voltage-gated calcium channels are potently blocked by the pyrethroid insecticide allethrin. J Pharmacol Exp Ther 2004;308:805–13.[Abstract/Free Full Text]
- Shafer TJ, Meyer DA. Effects of pyrethroids on voltage-sensitive calcium channels: a critical evaluation of strengths, weaknesses, data needs, and relationship to assessment of cumulative neurotoxicity. Toxicol Appl Pharmacol 2004;196:303–18.[ISI][Medline]
- McDonough JH Jr, Shih TM. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev 1997;21:559–79.[ISI][Medline]
- Baze WB. Soman-induced morphological changes: an overview in the nonhuman primate. J Appl Toxicol 1993;13:173–7.[ISI][Medline]
- Shih TM, McDonough JH. Organophosphorus nerve agents-induced seizures and efficacy of atropine sulfate as anticonvulsant treatment. Pharmacol Biochem Behav 1999;64:147–53.[ISI][Medline]
- Harrison PK, Sheridan RD, Green A, et al. A guinea pig hippocampal slice model of organophosphate-induced seizure activity. J Pharmacol Exp Ther 2004;310:678–86.[Abstract/Free Full Text]
- Clark JM, Brooks MW. Neurotoxicology of pyrethroids: single or multiple mechanisms of action? Environ Toxicol Chem 1989;8:361–72.
- He F, Chen S, Tang X, et al. Biological monitoring of combined exposure to organophosphorus and pyrethroids. Toxicol Lett 2002;134:119–24.[ISI][Medline]
- Szadkowski D. Toxicology of pyrethroids and their relevance to human health. Ann Agric Environ Med 1994;1:11–7.[Medline]
Top
Abstract
Introduction
