pralidoxime and Respiratory-Insufficiency

This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.

Topics: Acute Kidney Injury; Affect; Aged; Antidotes; Atropine; Chlorpyrifos; Female; Humans; Insecticides; Male; Mevinphos; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pneumonia, Aspiration; Pralidoxime Compounds; Psychotic Disorders; Respiratory Insufficiency; Retrospective Studies; Seizures; Shock; Survival Analysis; Treatment Outcome

Organophosphorus (OP) compounds inhibit central and peripheral acetylcholinesterase (AChE) activity, overstimulating cholinergic receptors and causing autonomic dysfunction (e.g., bronchoconstriction, excess secretions), respiratory impairment, seizure and death at high doses. Current treatment for OP poisoning in the United States includes reactivation of OP-inhibited AChE by the pyridinium oxime 2-pyridine aldoxime (2-PAM). However, 2-PAM has a narrow therapeutic index and its efficacy is confined to a limited number of OP agents. The bis-pyridinium oxime MMB4, which is a more potent reactivator than 2-PAM with improved pharmaceutical properties and therapeutic range, is under consideration as a potential replacement for 2-PAM. Similar to other pyridinium oximes, high doses of MMB4 lead to off-target effects culminating in respiratory depression and death. To understand the toxic mechanisms contributing to respiratory depression, we evaluated the effects of MMB4 (0.25-16 mM) on functional and neurophysiological parameters of diaphragm and limb muscle function in rabbits and rats. In both species, MMB4 depressed nerve-elicited muscle contraction by blocking muscle endplate nicotinic receptor currents while simultaneously prolonging endplate potentials by inhibiting AChE. MMB4 increased quantal content, endplate potential rundown and tetanic fade during high frequency stimulation in rat but not rabbit muscles, suggesting species-specific effects on feedback mechanisms involved in sustaining neurotransmission. These data reveal multifactorial effects of MMB4 on cholinergic neurotransmission, with the primary toxic modality being reduced muscle nicotinic endplate currents. Evidence of species-specific effects on neuromuscular function illustrates the importance of comparative toxicology when studying pyridinium oximes and, by inference, other quaternary ammonium compounds.

Topics: Acetylcholinesterase; Animals; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Female; Male; Muscles; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Rabbits; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Species Specificity; Synaptic Transmission

Organophosphate compounds (OP) are usual insecticides and may poison human beings in a suicide attempt or accidental exposure. They inhibit activity of cholinesterase. Poisoning may be enough sever for intensive care support. In this paper, we study the prevalence and management of sever cases as well.. We studied patients with OP poisoning, from November 2002 to November 2005 in Sina Hospital, Tabriz, Iran, retrospectively and found patients who needed intensive care. During 4 years study, we documented 80 patients who were hospitalized due to OP poisoning and used drugs. Treatment with intravenous atropine and pralidoxime was started as soon as possible. We did not administer pralidoxim for 20 patients due to late admission (5 patients) and unavailability of the medicine (15 patients).. Forty-five male and 35 female patients were enrolled in our study. The majority of the patients used OP for suicide attempt and 4 patients had accidental exposure. The mortality rate was 18% in patients who were treated with pralidoxim and patients without pralidoxim had a mortality rate of 21%. Ten patients were mechanically ventilated and the mortality rate was 50%. In patients without MV the mortality rate was 11.7%. The duration of intensive care stay was 7.1 +/- 2 days.. Organophosphate compounds poisoning is a serious and lethal condition and needs early diagnosis and appropriate treatment. In patients with respiratory failure the mortality is very high; therefore we recommended early diagnosis, careful monitoring and appropriate management of complications in reducing the mortality rate.

Topics: Adolescent; Adult; Age Distribution; Antidotes; Atropine; Chi-Square Distribution; Cohort Studies; Emergency Service, Hospital; Female; Humans; Incidence; Infusions, Intravenous; Insecticides; Iran; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds; Prognosis; Respiratory Insufficiency; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Distribution; Suicide, Attempted; Survival Analysis; Treatment Outcome

The authors report 2 cases of organophosphate poisoning which developed intermediate syndrome. The first case was a man who took an organophosphate insecticide, monocrotophos, and developed severe organophosphate poisoning. Respiratory support was needed. He was treated with atropine and 2-PAM. Weakness of neck muscles, proximal limb and respiratory muscle developed in the 3rd day after ingestion. By supportive treatment and careful monitoring, however, he recovered after 11 days of the poisoning. The second case was a lady who took dicrotophos. She developed severe organophosphate poisoning for which respiratory support was also needed High dose of atropine, but without 2-PAM, was administered. She developed bulbar palsy, proximal muscle and respiratory weakness 3 day after the ingestion. Ventilation support was needed for 13 days before weaning was successful. This report did not support an efficacy of pralidoxime (2-PAM) in alleviation of the intermediate syndrome, but aims to alert physicians to recognize the intermediate syndrome for which adequate respiratory care is the crucial key for its management.

Topics: Adult; Atropine; Female; Humans; Insecticides; Male; Muscle Weakness; Organophosphate Poisoning; Paralysis; Pralidoxime Compounds; Respiratory Insufficiency; Syndrome; Thailand; Time Factors

This investigation compared the efficacy of diazepam and the water-soluble prodiazepam-avizafone-in sarin poisoning therapy. Guinea pigs, pretreated with pyridostigmine 0.1 mg/kg, were intoxicated with 4LD(50) of sarin (s.c. route) and 1 min after intoxication treated by intramuscular injection of atropine (3 or 33.8 mg/kg), pralidoxime (32 mg/kg) and either diazepam (2 mg/kg) or avizafone (3.5 mg/kg). EEG and pneumo-physiological parameters were simultaneously recorded. When atropine was administered at a dose of 3 mg/kg, seizures were observed in 87.5% of the cases; if an anticonvulsant was added (diazepam (2 mg/kg) or avizafone (3.5 mg/kg)), seizure was prevented but respiratory disorders were observed. At 33.8 mg/kg, atropine markedly increased the seizure threshold and prevented early respiratory distress induced by sarin. When diazepam was administered together with atropine, seizures were not observed but 62.5% of the animals displayed respiratory difficulties. These symptoms were not observed when using avizafone. The pharmacokinetic data showed marked variation of the plasma levels of atropine and diazepam in different antidote combination groups, where groups receiving diazepam exhibited the lowest concentration of atropine in plasma. Taken together, the results indicate that avizafone is suitable in therapy against sarin when an anticonvulsant is judged necessary.

Topics: Animals; Anticonvulsants; Atropine; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Diazepam; Dipeptides; Drug Interactions; Electroencephalography; Guinea Pigs; Histocytochemistry; Muscarinic Antagonists; Nervous System Diseases; Pralidoxime Compounds; Prodrugs; Pyridostigmine Bromide; Respiratory Insufficiency; Sarin; Seizures

We describe a case of intermediate syndrome after chlorpyrifos ingestion in a toddler, despite a continuous pralidoxime infusion. A 16-month-old girl ingested a pesticide containing chlorpyrifos. She was brought to an Emergency Department where she became lethargic and tachycardic, and subsequently developed pulmonary edema requiring mechanical ventilation. Pralidoxime 150 mg i.v. was administered twice, and an infusion begun at 15 mg/kg/h. At 24.5 h post-ingestion the child had a normal neurologic examination, showed no signs of cholinergic excess, and was extubated successfully. At 27.5 h post-ingestion the child became flaccid, bradycardic and apneic. She was emergently re-intubated. The child's delayed onset of respiratory arrest and flaccid paralysis after an asymptomatic period is consistent with Intermediate Syndrome. This is an unusual case in that it occurred in a young child, was related to chlorpyrifos, and occurred despite continuous and adequate oxime therapy.

Topics: Chlorpyrifos; Cholinesterase Inhibitors; Cholinesterase Reactivators; Female; Humans; Infant; Insecticides; Paralysis; Poisoning; Pralidoxime Compounds; Respiration, Artificial; Respiratory Insufficiency

To examine the therapeutic effect of combined use of pralidoxime-Cl and atropine with artificial ventilation on respiratory muscle paralysis caused by omethoate poisoning in rats.. Rats were administered with same doses of 2LD(50) omethoate and then treated with atropine (10 mg/kg) to resist effectively chlolinergic symptoms. When the rats had slow respiratory frequency and breathed with difficulty, the trachea was intubated and artificial ventilation was carried out (except for group A). The rats in group B were continuously treated with atropine. The doses of pralidoxime-Cl for group C, D and E were 15 mg/kg, 20 mg/kg and 40 mg/kg respectively, given at the same time as artificial ventilation and 1, 2 and 3 hours later. The dose of atropine was reduced to 1/3 to 2/3 of the first dose so as to maintain the rats atropinized. If the rat survived beyond 60 minutes after withdrawal of artificial ventilation, the combined treatment was considered successful. The function of isolated phrenic diaphragm of the rats was observed with MS-302 analyses instrument physiologically and pharmacologically.. None of the rats in group B successfully withdraw from artificial ventilation. The rats in group C all successfully withdraw from artificial ventilation in 3 hours and the function of the isolated phrenic muscle remained good. The survival rats in group D and E were very low after withdrawal, even though the function of isolated phrenic muscle was good.. The therapeutic effect of the combined use of suitable dose of pralidoxime-Cl and atropine with artificial ventilation on respiratory muscle paralysis caused by omethoate poisoning in rats was significant. This measure can facilitate reversal of the function of poisoned diaphragm and reduced the death rate in poisoned rats.

Topics: Animals; Antidotes; Atropine; Diaphragm; Dimethoate; Disease Models, Animal; Drug Therapy, Combination; Female; Male; Pralidoxime Compounds; Rats; Rats, Wistar; Recovery of Function; Respiration, Artificial; Respiratory Insufficiency

Topics: Antidotes; Humans; Insecticides; Organophosphorus Compounds; Pralidoxime Compounds; Respiratory Insufficiency

Isolated rat diaphragm preparations treated with soman or with the irreversible and oxime resistant cholinesterase (ChE) inhibitor S27 showed a considerable recovery of neuromuscular transmission (NMT) during incubation with the (bis)pyridinium oximes HI-6, HGG-12, P2S and obidoxime. In the soman-treated preparations this NMT recovery was predominantly caused by reactivation of acetylcholinesterase (AChE) but in the S27-treated preparations it was caused by a direct (pharmacological) effect unrelated to enzyme reactivation. Atropinized rats were artificially ventilated after injection with 3 x LD50 soman for 3 h and then treated with HI-6, i.e. at a time when oxime reactivation of soman inhibited ChE is no longer possible. Nevertheless, these rats started to breathe spontaneously and 50-60% survived more than 24 h, whereas all control animals (saline instead of HI-6) died within 10 min after artificial ventilation was terminated. In such animals no significant reactivation of ChE activity at various time intervals following HI-6 treatment was found, either in the diaphragms or in the brains. There was a significant amount of NMT (50%) in vitro in diaphragms obtained from these animals. This NMT did not improve in vitro in the presence of HI-6 and was not inhibited by soman administered to the medium. It is concluded that in this case the NMT found was based on synaptic adaptation to the continued inhibition of ChE and that the survival of the animals might be due to a combination of this synaptic adaptation and central direct effects of HI-6.

Topics: Animals; Antidotes; Blood-Brain Barrier; Cholinesterase Reactivators; Diaphragm; In Vitro Techniques; Male; Neuromuscular Junction; Obidoxime Chloride; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Respiratory Insufficiency; Synaptic Transmission

Respiratory failure (RF) developed in 43 (40.2 percent) of 107 patients with acute organophosphate or carbamate poisoning; 22 (51.2 percent) died. The 64 patients who did not develop RF survived. All cases of RF developed within 96 hours after poisoning: within 24 hours in 35 patients (acute onset) and between 24 and 96 hours in eight patients (subacute onset). Severity of poisoning was the primary determinating factor for RF. Cardiovascular collapse and pneumonia were also associated with RF. In 19 patients with cardiovascular collapse, 17 had acute onset of RF and two had subacute onset. In 28 patients with pneumonia, 17 developed acute onset of RF and eight developed subacute onset. No organophosphorus compound caused RF more frequently than another. The duration of ventilator support for subacute RF was significantly longer than for acute RF (287 +/- 186 vs 115 +/- 103 hours, p = 0.02). The use of pralidoxime did not reduce the incidence of RF. We found that severity of poisoning, cardiovascular collapse, and pneumonia were the predisposing factors to RF. The golden time for treatment of acute organophosphate or carbamate poisoning was the initial 96 hours. No RF occurred after this time. Aggressive treatment and prevention of the above three factors will reduce the incidence of RF, or in other words, reduce the mortality.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antidotes; Atropine; Carbamates; Child; Child, Preschool; Female; Humans; Infant; Insecticides; Male; Middle Aged; Organophosphorus Compounds; Pneumonia; Pralidoxime Compounds; Respiration, Artificial; Respiratory Insufficiency

Topics: Acute Disease; Adolescent; Adult; Antidotes; Child; Child, Preschool; Cholinesterases; Female; Humans; Insecticides; Intensive Care Units; Malaysia; Male; Middle Aged; Organophosphorus Compounds; Pralidoxime Compounds; Respiratory Distress Syndrome; Respiratory Insufficiency