Severe Organophosphate Research Articles

Jimson weed extract as a protective agent in severe organophosphate toxicity.

Treatment of patients following an organophosphate (OP) exposure can deplete a hospital's entire supply of atropine. Given the possibility of multiple severe exposures after a terrorist attack using OP nerve agents, there exists a need for either greater atropine stores or the development of alternative antidotes. Jimson weed (Datura stramonium) contains atropine and other anticholinergic compounds and is common and readily available. It is used recreationally for its central anticholinergic effects and is made easily into an extract by boiling the crushed seeds. The extract has rapid onset of effects and may be useful for treatment of OP poisoning. To determine whether pretreatment with an easily stored and prepared Datura seed extract (DSE) will increase survival following a severe OP poisoning. Datura stramonium seeds were collected, crushed, and then heated in water to make a 2-mg/mL atropine solution (100 seeds contain approximately 6 mg of atropine or 0.007 mg/seed). Male rats were randomized to pretreatment with either saline (n = 10) or 7.5 mg/kg DSE (n = 10) given as a single intraperitoneal injection 5 minutes prior to a subcutaneous injection of 25 mg/kg of dichlorvos. The endpoint was time to death recorded by a blinded observer. The Kaplan-Meier estimates of the 24-hour survival rate was 90% (95% CI = 56% to 100%) for the DSE-pretreated group and 10% (95% CI = 0% to 45%) for the control group. The log-rank test revealed a statistically significant longer survival for the Datura-treated animals (p = 0.0002). Median survival time was 22 minutes 30 seconds for the control group and greater than 24 hours for the DSE-pretreated group. Pretreatment with DSE significantly increases survival following severe dichlorvos exposure.

Jimson Weed Extract as a Protective Agent in Severe Organophosphate Toxicity

Jimson Weed Extract as a Protective Agent in Severe Organophosphate Toxicity

Diazepam Inhibits Organophosphate‐induced Central Respiratory Depression

Abstract Objectives: Current evidence suggests that mortality from acute organophosphate (OP) poisoning is partially mediated through central nervous system (CNS) respiratory center depression (CRD). However, the exact mechanism of OP‐induced CRD is unknown. In these studies, the authors investigated the hypothesis that OP‐induced CRD is the result of overstimulation of CNS respiratory centers. Methods: Wistar rats received prophylaxis with either normal saline (controls), atropine, the peripherally acting anticholinergics glycopyrrolate (GLYC), ipratropium bromide (IB), or the CNS respiratory center attenuator diazepam. To determine if a dual CNS/peripheral cholinergic mechanism is responsible for animal death, two additional groups received combination treatment with diazepam plus either IB or GLYC. All treatments were completed 5 minutes before OP with subcutaneous dichlorvos. Differences in 10‐minute and 24‐hour mortality were assessed by the Fisher exact test. Results: Dichlorvos poisoning resulted in profound fasciculations without obvious seizure in all cohorts. In controls and animals treated with peripherally acting anticholinergics, fasciculations were followed by sedation and respiratory arrest (0% 10‐minute survival in all cohorts). In contrast, pretreatment with either atropine or diazepam significantly improved 10‐minute survival (100% and 44%, respectively). Although GLYC or IB afforded no protection when given alone, when delivered in conjunction with diazepam, the combination significantly improved survival (both groups 88% at 24 hours), suggesting a dual CNS/pulmonary muscarinic mechanism of lethality. Conclusions: The central respiratory depressant diazepam paradoxically attenuates organophosphate‐induced respiratory depression, and when combined with peripherally acting anticholinergic agents, reduces mortality in a rat model of severe acute OP poisoning.

Diazepam inhibits organophosphate-induced central respiratory depression.

Current evidence suggests that mortality from acute organophosphate (OP) poisoning is partially mediated through central nervous system (CNS) respiratory center depression (CRD). However, the exact mechanism of OP-induced CRD is unknown. In these studies, the authors investigated the hypothesis that OP-induced CRD is the result of overstimulation of CNS respiratory centers. Wistar rats received prophylaxis with either normal saline (controls), atropine, the peripherally acting anticholinergics glycopyrrolate (GLYC), ipratropium bromide (IB), or the CNS respiratory center attenuator diazepam. To determine if a dual CNS/peripheral cholinergic mechanism is responsible for animal death, two additional groups received combination treatment with diazepam plus either IB or GLYC. All treatments were completed 5 minutes before OP with subcutaneous dichlorvos. Differences in 10-minute and 24-hour mortality were assessed by the Fisher exact test. Dichlorvos poisoning resulted in profound fasciculations without obvious seizure in all cohorts. In controls and animals treated with peripherally acting anticholinergics, fasciculations were followed by sedation and respiratory arrest (0% 10-minute survival in all cohorts). In contrast, pretreatment with either atropine or diazepam significantly improved 10-minute survival (100% and 44%, respectively). Although GLYC or IB afforded no protection when given alone, when delivered in conjunction with diazepam, the combination significantly improved survival (both groups 88% at 24 hours), suggesting a dual CNS/pulmonary muscarinic mechanism of lethality. The central respiratory depressant diazepam paradoxically attenuates organophosphate-induced respiratory depression, and when combined with peripherally acting anticholinergic agents, reduces mortality in a rat model of severe acute OP poisoning.

Jimsonweed (Datura stramonium) Seed Extract as a Protective Agent in Severe Organophosphate Poisoning

Jimsonweed (Datura stramonium) Seed Extract as a Protective Agent in Severe Organophosphate Poisoning

Early death due to severe organophosphate poisoning is a centrally mediated process.

To distinguish whether early death from severe organophosphate (OP) poisoning with dichlorvos is mediated through peripheral or central nervous system (CNS) actions. Wistar rats (n = 72) were randomized to pretreatment with either: normal saline (controls), peripheral anticholinergics (glycopyrrolate [low, medium, or high dose] or nebulized ipratropium bromide), or CNS + peripherally acting anticholinergics (diphenhydramine, nebulized atropine, or injected atropine). All treatments were given prior to a subcutaneous injection of 25 mg/kg dichlorvos (n = 8 per group). Survival was assessed at 10 minutes (early death) and 24 hours (delayed death). Kaplan-Meier (95% confidence intervals [95% CIs]) and chi-squared analysis was then performed to determine differences between treatments. Regardless of treatment, all animals exhibited profound nicotinic effects (fasciculations) without obvious seizures within 2 minutes of poisoning. In rats pretreated with peripherally acting agents, the fasciculations were rapidly followed by reduced motor activity, sedation, and death. Mortality at 10 minutes for saline controls, glycopyrrolate, and ipratropium was 88%, 96%, and 100%, respectively. The single control animal surviving beyond 10 minutes went on to develop peripheral cholinergic manifestations, including hypersalivation, urination, and defecation. Only one of 24 animals treated with injected atropine, nebulized atropine, or diphenhydramine died during the early phase of poisoning; all others survived to 24 hours (p < 0.01). Death in acute, severe OP poisoning is prevented by pretreatment with anticholinergic agents that cross the blood-brain barrier, but not by agents with only peripheral actions. Early death due to OP poisoning appears to be a centrally mediated process.

Early Death Due to Severe Organophosphate Poisoning Is a Centrally Mediated Process

Early Death Due to Severe Organophosphate Poisoning Is a Centrally Mediated Process

Diphenhydramine as a Protective Agent in a Rat Model of Acute, Lethal Organophosphate Poisoning

Objective: To evaluate the effects of diphenhydramine chloride (DPH) on mortality in a rat model of acute, severe organophosphate poisoning (OP).Methods: Wistar rats (n = 40) were randomized to pretreatment with either normal saline (controls), 5 mg/kg atropine, 3 mg/kg DPH, 15 mg/kg DPH, or 30 mg/kg DPH given as a single intramuscular injection 5 minutes prior to a subcutaneous injection of 25 mg/kg dichlorvos (n = 8 per group). The primary endpoint was 10‐minute survival. Survival at 24 hours was a secondary endpoint. Comparison of survival rates between groups was carried out by ANOVA and the Student‐Newman‐Keuls test. Results: Dichlorvos exposure resulted in profound fasciculations within 2 minutes of injection in all cohorts. In controls, fasciculations were followed by respiratory arrest within 10 minutes (0% survival). The rats receiving atropine pre‐treatment exhibited similar fasciculations (nicotinic effects) without subsequent respiratory arrest, resulting in a significant improvement in survival (88%, p &lt; 0.001). The DPH‐treated rats exhibited a significant dose‐dependent reduction in mortality, with the 3 mg/kg, 15 mg/kg, and 30 mg/kg groups demonstrating 0%, 25%, and 100% survival, respectively. There was no additional mortality between 10 minutes and 24 hours in any group. There was no significant difference in survival between the high‐dose DPH and the atropine groups. Conclusions: Diphenhydramine chloride significantly reduced mortality in rats with acute, severe dichlorvos exposure.

Early Death Due to Severe Organophosphate Poisoning Is a Centrally-mediated Process

Early Death Due to Severe Organophosphate Poisoning Is a Centrally-mediated Process

Diphenhydramine as a Protective Agent in Severe Organophosphate Poisoning

Diphenhydramine as a Protective Agent in Severe Organophosphate Poisoning

Aggressive atropinisation and continuous pralidoxime (2-PAM) infusion in patients with severe organophosphate poisoning: experience of a northwest Indian hospital.

The aim of the study was to find whether continuous pralidoxime (2-PAM) infusion along with aggressive atropinisation improves the outcome in patients with severe organophosphate poisoning who require assisted ventilation. Sixteen patients admitted to the respiratory intensive care unit (RICU) with severe organophosphate poisoning and requiring assisted ventilation were included in the study. The compounds involved were phorate (six), dichlorvos (four), oxydimeton methyl (one), monocrotophos (one), methyl parathion (one) and in three it was unknown. After decontamination, they were given intravenous (iv) bolus atropine 5 mg at onset and then 2.5 mg every 5-10 min till atropinisation was achieved, and then maintained either by intermittent bolus doses or by continuous infusion if the required dose was large. They were also given continuous iv infusion of 2-PAM in dose of 7.5 mg/ kg body weight/h (maximum 500 mg/h) after an initial bolus dose of 2 g. The mean (+/-S.D.) dose of atropine was 735.02 +/- 742.98 mg (range 85-3000 mg) with maximum dose on day 1. The mean (+/-S.D) duration of 2-PAM infusion was 96.4+/-49.4 h (range 10-216 h). The mean (+/-S.D) duration of mechanical ventilation (MV) was 131.5 +/- 95.65 h (range 4-336 h). Fourteen patients could be successfully extubated and two died of bronchopneumonia and sepsis (mortality 12.5%). Continuous 2-PAM infusion along with aggressive atropinisation after initial decontamination improved the outcome but not the duration of MV in severely intoxicated patients with organophosphate compounds who required assisted ventilation in this case series.

Spectral analysis of systemic arterial pressure and heart rate signals of patients with acute respiratory failure induced by severe organophosphate poisoning.

Spectral analysis of systemic arterial pressure (BP) and heart rate (HR) signals may be an alternative prognostic tool for predicting patient outcome in the intensive care unit (ICU). We evaluated the applicability of the same analysis in the emergency department for predicting mortality in patients with acute respiratory failure induced by severe organophosphate poisoning. Prospective collection of data from 14 emergency service patients. Emergency service at a large, university-affiliated medical center. Consecutive patients who, after attempting suicide by ingesting organophosphates, were admitted to the ICU of the emergency service with acute respiratory failure and remained for > or =2 days None. Demographic and survival data and day 1 Acute Physiology and Chronic Health Evaluation (APACHE) II and Glasgow Coma Scale scores were recorded. Continuous, on-line, real-time spectral analysis of BP and HR signals was carried out during the first 12 hrs after admission. We then computed the total sum of power density during this period of the low-frequency (0.04-0.15 Hz) and very low-frequency (0.004-0.04 Hz) components in the BP and HR spectra, along with the averaged values of mean BP and HR. Eight patients who recovered exhibited vigorous power in the low-frequency and very low-frequency components of their BP and HR signals. There was a significant reduction in the power density of those four spectral components in three patients who eventually died. Three patients discharged in a vegetative state manifested significantly reduced power in the low-frequency component in their BP spectra, with maintained power in the other three spectral components. APACHE II and Glasgow Coma Scale scores of the recovered patients were discernibly different from those of patients who eventually died or who became vegetative. None of the 14 patients showed appreciable differences in mean BP, mean HR, erythrocyte or plasma cholinesterase concentration, or atropine requirement during the first 24 hrs. The low-frequency and very low-frequency components of BP and HR signals may be a sensitive alternative index for early prediction of mortality in patients with acute respiratory failure induced by severe organophosphate poisoning.

多彩な神経症状を呈した有機リン中毒の１例

A 57-year-old man developed unconsciousness, miosis and tetraplegia with fasciculation due to acute organophosphate (OP) intoxication. His symptoms improved and he revived with a transient alpha coma, rigidity, mirror-movement-like reaction and tetraplegia dominating in the lower extremities, but these signs finally subsided. As acetylcholinesterase was thought to be rich in the medial frontal lobe, basal ganglia and brainstem, the disturbance of these areas due to OP may lead to the neurological focal signs mentioned above. Thus we need pay attention to these focal signs in the case of severe acute OP intoxication.

The clinical significance of hyperamylasemia in organophosphate poisoning.

Hyperamylasemia with a presumptive diagnosis of acute pancreatitis has been reported following organophosphate poisoning but there are no large-scale studies incorporating more specific diagnostic criteria. Retrospective review of the medical records of 159 patients with a diagnosis of organophosphate poisoning over 3 years. Serum amylase, pancreatic amylase, salivary amylase, lipase and cholinesterase levels, and the clinical manifestations were analyzed. Serum amylase data was available for 121 of the 159 study patients. Hyperamylasemia (amylase > or = 360 U/L) was found in 44 patients (36%). Lipase was measured in 28 patients with hyperamylasemia; 9 of 28 had hyperlipasemia (lipase > or = 380 U/L). The finding of hyperamylasemia was closely related to clinical severity and presence of shock. A presumptive diagnosis of painless acute pancreatitis was diagnosed by hyperlipasemia associated with hyperamylasemia, clinical severity, serum LDH, and leukocyte counts. Two patients with presumptive pancreatitis died. Shock, coma, and hypoalbuminemia were the factors predicting fatality. Hyperamylasemia is frequent in severe organophosphate poisoning. However, hyperamylasemia is not synonymous with acute pancreatitis and pancreatic amylase is not a reliable parameter in the diagnosis of organophosphate-induced pancreatitis due to its low sensitivity and specificity. Lipase assay is indicated in patients with hyperamylasemia for early diagnosis of pancreatitis. Proper image studies and even pathological examination are also needed to confirm the extent of pancreatic injury. With prompt diagnosis and appropriate treatment, a complete recovery can be anticipated unless the patient has otherwise unrelated complications.

反復活性炭注入を行ったｆｅｎｔｈｉｏｎによる重症有機リン中毒の幼児例

A child with severe organophosphate (fenthion) poisoning was successfully treated by repeated administration of activated charcoal with infusion of atropine sulfate and PAM (pyridine 2-aldoxime methiodine). A 19-month-old girl ingested fenthion and was admitted 1.5 hours later. Her serum cholinesterase level was 59IU/l on admission and diminished to 2.7% of the lower limit of normal range over the subsequent 4 days. It then rose gradually over the next 10 days and the clinical symptoms also improved. The serum fenthion value reached its maximal level of 0.66μg/ml at the time of a seizure that occurred 20 hours after exposure, and the half-life of fenthion was 11 hours. The patient recovered from the poisoning smoothly and there were no signs or symptoms indicating a relapse. Assuming that repeated administration of activated charcoal inhibits reabsorption of organophosphate in the entero-hepatic circulation, we can easily understand the fenthion value course or this clinical course. Infusion of atropine sulfate every 2-3 hours was effective in controlling muscarinic reactions, but PAM was not in nicotinic and other toxic reactions. The patient's conciousness was transiently dulled by chloral hydrate during recovery. The use of chloral hydrate should be avoided in the acute phase, because it induces transient disturbances of consiousness.

Paralytic ileus as a complication of atropine therapy following severe organophosphate poisoning

A 32-year-old man presented with symptoms of severe organophosphate poisoning and required an atropine infusion for 5 weeks. We believe the development of a paralytic ileus occurred as a rare feature of atropine toxicity when other signs were masked by the underlying condition. The onset of a paralytic ileus coincided with a spontaneous increase in red cell cholinesterase levels and may be an early sign of recovery from organophosphate poisoning.

Organophosphate Poisoning: Peripheral Vascular Resistance – A Measure of Adequate Atropinization

We report severe organophosphate poisoning complicated by hypotension and ischemic sequelae in two patients with pre-existing vascular disease. Both patients had a low total peripheral resistance and high cardiac output that were significantly reversed by doses of atropine in excess of those required to control other muscarinic symptoms. Cerebral infarcts and gangrene requiring a below knee amputation were complications of the poisonings. It is proposed that the ischemic complications are due to paradoxical vasoconstriction by acetylcholine at sites of endothelial injury. One patient, who had taken fenthion, also had a significantly delayed peak and prolonged, 2-3 week, systemic toxicity. We propose that stability of the plasma cholinesterase at 6 to 8 h after temporarily suspending oxime provides a rapid guide to the duration of therapy, especially in patients whose complications make clinical assessment difficult.

A case of acute poisoning due to organophosphate insecticide

A case of acute severe organophosphate poisoning by deliberate self administration is reported. The patient required intensive therapy for 30 days. Unusual features of the case were the avoidance of atropine, because of the high risk of ventricular fibrillation, and the ineffectiveness of pralidoxime.

High pancuronium sensitivity of axonal nicotinic‐acetylcholine receptors in humans during organophosphate intoxication

The effect of low-dose pancuronium on neuromuscular transmission was studied in 2 patients during the early and late stages of severe organophosphate intoxication. Single evoked compound muscle action potentials (CMAP) were followed by repetitive discharges and a decrement-increment (D-I) phenomenon with 10-, 20-, and 50-Hz supramaximal nerve stimulation. Intravenous pancuronium, 1 mg, abolished the D-I phenomenon, while the repetitive discharges of the CMAP were only partially reduced. It is postulated, that the disappearance of the D-I phenomenon with persistence of the CMAP repetitive discharges results from blockade of nicotinic-acetylcholine receptors located on the terminal axon responsible for stimulus-induced antidromic backfiring. This response to a very low dose of pancuronium indicates a high sensitivity of the axonal nicotinic-acetylcholine receptor to pancuronium in humans, as had been previously postulated from animal experiments.

Der Effekt von Neostigmin an der motorischen Endplatte beim Intermediärsyndrom der Alkylphosphatvergiftung

A patient with severe organophosphate intoxication received Neostigmine 1 mg IV during the intermediate syndrome. This dose resulted clinically and neurophysiologically in a marked deterioration of neuro-muscular transmission. This effect of neostigmine on the neuromuscular block during the intermediate syndrome (deterioration) differs from its effect on a similar pattern (improvement), which is seen in the delayed neuropathy following organophosphate exposure. The administration of therapeutic doses of cholinesterase inhibitors in patients with a reduced safety margin due to inhibition of endplate acetylcholinesterase may be dangerous.