Caspases as prognostic markers and mortality predictors in acute organophosphorus poisoning.

BACKGROUND: Organophosphorus (OP) compounds have been widely available for decades in agriculture for crop protection and as cheap pest controllers, which increases the rate of exposure and poisoning cases. Using serum cholinesterase as prognostic markers for the acute OP toxicity is controversial; therefore, we aim to find out prognostic biomarkers that best correlate with mortality and outcomes of patients with acute OP toxicity. Levels of serum oxidative stress biomarkers (malondialdehyde (MDA) and total antioxidant capacity (TAC)) and activity of the apoptotic biomarkers (caspase 3 and caspase 9) and pseudo-cholinesterase (p.ChE) were performed. Also, we evaluated the apoptotic capacity through determining the genotoxic effects and chromosomal abnormalities among OP intoxicated patients. RESULTS: We found the activity of caspases and serum MDA and TAC were significantly increased after OP poisoning and decreased after the appropriate atropine and oxime treatment course. The ROC curve suggested caspases as mortality and outcome predictive markers for acute OP poisoning patients. However, OP poisoning cases before treatment showed significant DNA damage, and they did not show any chromosomal aberration. CONCLUSION: The mentioned results strongly suggest apoptotic-related markers (caspase 3, caspase 9) as prognostic markers for evaluation of the treatment, outcomes, and mortality rate in the acute OP toxicity patients.

Multiomic Analysis of Zebrafish Models of Acute Organophosphorus Poisoning With Different Severity.

Organophosphorus compounds are acetylcholinesterase inhibitors used as pesticides and chemical warfare nerve agents. Acute organophosphorus poisoning (acute OPP) affects 3 million people, with 300 000 deaths annually worldwide. Severe acute OPP effects include overstimulation of cholinergic neurons, seizures, status epilepticus, and finally, brain damage. In a previous study, we developed 3 different chemical models of acute OPP in zebrafish larvae. To elucidate the complex pathophysiological pathways related to acute OPP, we used integrative omics (proteomic, transcriptomics, and metabolomics) on these 3 animal models. Our results show that these stochastic, apparently disparate morphological phenotypes can result from almost linear concentration-response variations in molecular levels. Results from the multiomics analysis strongly suggest that endoplasmic reticulum stress might play a central role in the pathophysiology of severe acute OPP, emphasizing the urgent need of further research on this molecular pathway. Endoplasmic reticulum stress could be an important therapeutic target to be included in the treatment of patients with severe acute OPP.

Comprehensive characterization of neurochemicals in three zebrafish chemical models of human acute organophosphorus poisoning using liquid chromatography-tandem mass spectrometry.

There is a growing interest in biological models to investigate the effect of neurotransmitter dysregulation on the structure and function of the central nervous system (CNS) at different stages of development. Zebrafish, a vertebrate model increasingly used in neurobiology and neurotoxicology, shares the common neurotransmitter systems with mammals, including glutamate, GABA, glycine, dopamine, norepinephrine, epinephrine, serotonin, acetylcholine, and histamine. In this study, we have evaluated the performance of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the multiresidue determination of neurotransmitters and related metabolites. In a first step, ionization conditions were tested in positive electrospray mode and optimum fragmentation patterns were determined to optimize two selected reaction monitoring (SRM) transitions. Chromatographic conditions were optimized considering the chemical structure and chromatographic behavior of the analyzed compounds. The best performance was obtained with a Synergy Polar-RP column, which allowed the separation of the 38 compounds in 30 min. In addition, the performance of LC-MS/MS was studied in terms of linearity, sensitivity, intra- and inter-day precision, and overall robustness. The developed analytical method was able to quantify 27 of these neurochemicals in zebrafish chemical models for mild (P1), moderate (P2), and severe (P3) acute organophosphorus poisoning (OPP). The results show a general depression of synaptic-related neurochemicals, including the excitatory and inhibitory amino acids, as well as altered phospholipid metabolism, with specific neurochemical profiles associated to the different grades of severity. These results confirmed that the developed analytical method is a new tool for neurotoxicology research using the zebrafish model.

Pharmacoeconomic Analysis of Penehyclidine Hydrochloride and Atropine in the Treatment of Acute Organophosphorus Poisoning / 中国药房

OBJECTIVE:To evaluate the economics of penehyclidine hydrochloride and atropine in the treatment of acute organophosphorus poisoning (AOPP).METHODS:The information of 118 AOPP patients were collected and divided into group A (59 cases) and B (59 cases) according to therapy plan.There were 22 cases of mild poisoning,20 cases of moderate poisoning and 17 cases of severe poisoning in group A.There were 21 mild cases,21 moderate cases and 17 severe cases in group B.Based on routine treatment,group A was given Penehyclidine hydrochloride injection intramuscularly with initial dose of 1 mg (mild),2 mg (moderate) and 4 mg (severe).Group B was given Atropine sulfate injection intravenously,with initial dose of 2 mg (mild),5 mg (moderate) and 10 mg (severe).Both received maintenance treatment according to patients condition and stopped taking medicine after symptoms disappeared.Clinical efficacies,the time of acetylcholinesterase recovery and ADR were observed in 2 groups.The economics of therapy plans for mild,moderate and severe poisoning were evaluated in 2 groups by cost-effectiveness analysis.RESULTS:There was no statistical significance in total response rate of mild poisoning or the time of acetylcholinesterase recovery between 2 groups (P＞0.05).Total effective rates of moderate and severe poisoning in group A were significantly higher than group B,and the time of acetylcholinesterase recovery was significantly shorter than group B,with statistical significance (P＜0.05).There was no statistical significance in the incidence of ADR in mild,moderate and severe poisoning patients (P＞0.05).Cost-effectiveness ratio of penehyclidine hydrochloride was similar to that of atropine in mild poisoning patients;that of penehyclidine hydrochloride were significantly lower than that of atropine in moderate and severe patients.It was inline with the results of sensitivity analysis.CONCLUSIONS:Based on routine treatment,penehyclidine hydrochloride is similar to atropine in therapeutic efficacy of AOPP and the time of acetylcholinesterase recovery.For moderate and severe AOPP patients,penehyclidine hydrochloride is significantly better than atropine in improving therapeutic efficacy and the time of acetylcholinesterase recovery.The safety of 2 drugs are satisfactory;penehyclidine hydrochloride possesses cost-effectiveness advantage.

To identify morbidity and mortality predictors in acute organophosphate poisoning.

BACKGROUND: Organophosphorus poisoning remains an important cause of morbidity and mortality, but no definite parameters have been identified as predictors of outcome. Prediction of morbidity at presentation might help in decision making in places of limited resources like rural settings in developing countries. MATERIALS AND METHODS: A total of 76 cases were included in this retrospective cohort study. Logged relative risk of requirement of mechanical ventilation and hospital stay >7 days was measured in patients with serum acetylcholinesterase (s. acetylcholinesterase) <1000 versus >1000, presenting in <2 h versus ≥ 2 h after exposure, with Glasgow Coma Scale (GCS) ≤12 versus >12 and in patients with SpO2 <85% versus ≥85% at room air at presentation. RESULTS: S. acetylcholinesterase <1000, time elapsed after ingestion to presentation ≥ 2 h and SpO2 (at room air) at presentation <85% were found to have positive association with requirement of ventilation. GCS ≤ 12 had a significant association with both requirement of ventilation and hospital stay >7 days. CONCLUSION: S. acetylcholinesterase, SpO2 at room air, GCS, and duration of exposure at presentation can be used to identify the requirement of special care in acute organophosphorus poisoning. This can aid in decision making regarding admission to intensive care unit and referral in the places with limited resources.

Acute organophosphorus poisoning.

Acute organophosphorus poisoning continues to be a detrimental problem and a potential cause of mortality especially in developing countries. Inhibition of acetylcholinesterase enzyme is the main mechanism of toxicity of such pesticides and measurement of acetylcholinesterase activity is the commonly used laboratory diagnosis approved for the purpose. It is now proved beyond any doubt that early intervention is beneficial for cases of acute organophosphorus poisoning and, therefore, considerable current interest has been generated for development of point of care testing tool for screening of the same. However, to the best of our knowledge so far the matter is not reviewed from the view of point of care testing tool development. In this paper, this subject is reviewed highlighting the methodological aspects and point of care testing tool development in the context of organophosphorus poisoning.

The effects of Xuebijing injection on ATPase of diaphragm in rats with acute organophosphorus poisoning / 中国中西医结合急救杂志

Objective To investigate the changes in ATPase activity of diaphragm in rats with acute organophosphorus poisoning (AOPP) and to explore the effect of Xuebijing injection on the ATPase activity. Methods 24 clean healthy Spraue-Dawley(SD)rats were divided into control group,model group and Xuebijing treatment group by means of random number table,with 8 rats in each group. AOPP model was established by intra-gastrical administration of 50 mg/kg oxide dimethoate. In Xuebijing treatment group,after oxide dimethoate administration,intraperitoneal injection of Xuebijing(10 mL/kg)was given at the same time,while in control group and model group,equal amount of normal saline(NS)was injected via the same route. The rats were sacrificed at 6 hours after model formation,and their diaphragms were taken sterilely. The activities of Na+-K+-ATPase and Ca2+-ATPsae of diaphragms were detected by enzyme linked immunosorbent assay(ELISA). The histopathological changes in diaphragms of rats were observed with light microscopy. Results 6 hours after intoxication,the diaphragm Na+-K+-ATPase activity of rats in model group was markedly lower than that in control group(mmol?h-1?g-1:5.22±0.74 vs. 9.98±0.37,P<0.01),while the Na+-K+-ATPase activity in Xuebijing treatment group(6.93±1.14) was markedly higher than that in model group(P<0.05). The diaphragm Ca2+-ATPase activity of rats in model group was markedly lower than that in control group(mmol?h-1?g-1:7.45±0.74 vs. 12.08±0.74,P<0.01),while the Ca2+-ATPase activity in Xuebijing treatment group(9.35±1.67)was obviously higher than that in model group(P<0.05)after intoxication for 6 hours. Light microscope observation indicated that there were swelling and necrosis in diaphragm in model group,while in Xuebijing treatment group no necrosis was found. Conclusion The diaphragm was degenerated and necrotic in AOPP rats,Xuebijing injection can lessen the injury in such rats,and the curative effect may be related to the improvement of the Na+-K+-ATPase and Ca2+-ATPsae activities of diaphragm.

Prognostic value of APACHE Ⅱ score in patients with severe acute organophosphorus poisoning / 重庆医学

Objective To explore the prognostic value of APACHE Ⅱscore in patients with Severe acute organophosphorus poi-soning .Methods 42 patients with Severe acute organophosphorus poisoning ,in which 34 cases survived ,8 cases dead ,were select-ed .The APACHE Ⅱscores of patients in first 24 h of admission were collected ,and receiver operating characteristic curves (ROC curve) were drawn .Results APACHE Ⅱ score of the 42 patients with Severe acute organophosphorus poisoning was 18 ~30 (20 .11 ± 6 .32) ,in which the survival group was(16 .10 ± 3 .12) ,the dead group was(28 .01 ± 4 .46) (P<0 .01) .With the increase of APACHE Ⅱ score ,the fatality rate gradually increased .The total area under the ROC curves of APACHE Ⅱ score for death judgment was 0 .922 ,APACHE Ⅱ score of 21 .2 was the best diagnostic point ,the sensitivity was 95% ,and specificity was 89% . Conclusion The APACHE Ⅱscore could predict severity of patients with Severe acute organophosphorus poisoning ,and APACHEⅡscore ≥21 .2 could be used as the prognosis for death of the patients .

Influence of hemoperfusion frequency on therapeutic effect and prognosis of patients with severe acute organophosphorus poisoning / 中国中西医结合急救杂志

Objective To discuss the correlations between hemoperfusion(HP) times and therapeutic effects/prognosis in patients with severe acute organophosphorus poisoning(AOPP). Methods According to the frequency of HP,82 patients with severe AOPP were divided into three groups:non HP(25 cases),HP1(27 cases) and HP2(30 cases)groups. The non HP group received only routine treatment,on the basis of routine treatment,the HP1 group accepted once HP within 12 hours after poisoning and the HP2 group underwent twice or more times of HP,the interval between each time being 24 hours. The comparisions of clinical indexes,incidences of complications and rates of mortality among the three groups were performed. Results With the increase of HP times,the dosages of atropine and pralidoxime chloride were significantly reduced,the times of serum cholinesterase(ChE)activity recovery,consciousness recovery,hospitalization and mechanical ventilation were significantly shortened,the score of acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ)score in 48 hours after admission,incidence of complications and mortality were evidently decreased(all P<0.05). Compared with those in HP1 group,the dosages of atropine(mg:164.57±68.82 vs. 256.81±97.06)and pralidoxime chloride(mg:6.95±1.40 vs. 8.76±1.64) in HP2 group were significantly reduced,the times of ChE activity recovery(day:9.03±2.46 vs. 10.96±3.44), consciousness recovery(hour:23.83±6.29 vs. 39.93±8.24),hospitalization(hour:9.57±2.39 vs. 11.52±3.02) and mechanical ventilation(hour:40.50±16.55 vs. 65.74±18.88)in HP2 group were significantly shortened;APACHEⅡscore during 48 hours after admission(11.97±3.47 vs. 14.26±2.88)was obviously decreased,and the incidences of complications,such as intermediate syndrome(10.0% vs. 18.5%),rebound phenomenon(3.3% vs. 25.9%),arrhythmia(13.3%vs. 44.4%),multiple organ dysfunction syndrome(MODS,6.7%vs. 29.6%)and mortality rate(6.7% vs. 18.5%)in HP2 group were markedly decreased(all P<0.05). Conclusion It is recommendable that combined with routine treatment,early and multiple HP application would enhance the therapeutic effect and decrease the mortality in patients with severe AOPP.

Analysis of therapeutic effect of lipid emulsion on acute organophosphorus poisoning and acute lung injury in rats / 中华急诊医学杂志

Objective To explore the therapeutic effect of lipid emulsion on acute organophosphorus poisoning and its consequence of acute lung injury. Methods A total of 48 sealant - grade Sprague-Dawley (SD) rats were randomly divided into four groups A,B,C,D,namely saline control group,lipid emulsion control group,the conventional therapy group and lipid emulsion administration group. After dichlorvos (DDVP) 11 mg/kg was given by intra-peritoneal injection,if there was no loss of DDVP during the injection process,the model of poisoning was considered to be made successfully.Then the rat models in four groups were respectively treated:with normal saline (5 ml/kg) intravenous injection in group A,lipid emulsion (5ml/kg) intravenous injection in group B,atropine (5 mg/kg) and pralidoxime chloride (40 mg/kg) intramuscular injection in group C,and combined use of lipid emulsion (5 ml/kg) with atropine and pralidoxime chloride in group D after administration of DDVP by intra-peritoneal injection.The activity of cholinesterase (CHE) in blood was detected before and 0.5 h,2 h and 4 h after DDVP poisoning. The clinical manifestations,the survival of rats,the wet weight of rat' s lung and the pathological changes of the lung tissue were observed within following 24 h. The rates of survival and symptoms of rats were compared between paired groups by using the x2 test,and the mean values of biomarkers were compared paired groups by using t test. Results In groups A and B,the intensity of muscular fasciculation and salivation were more severe and appeared sooner after DDVP exposure in comparison with groups C and D leading to lower survival rates in group A and B. Compared with group C,the rate of 24 h survival was higher and the intensity of muscular fasciculation was weaker in group D ( P ＜ 0.05 ).In group A and group B,the 24-hour survival rates were 1/12 and 2/12,respectively ( P ＜ 0.05 ).The levels of CHE in blood significantly decreased after DDVP poisoning ( P ＜ 0.05 ).There was no significant difference in activity of CHE between group B and group A,and in groups C and D,the levels of CHE in blood were not significantly higher than that in the group B 0.5 h after DDVP poisoning ( P ＜ O.05 ).In groups C and D,the activity of CHE in blood was significantly higher compared with group A and B,and that in group D was higher compared with C,and that in group B was higher compared with A 2 and 4 hours after DDVP poisoning ( P ＜ 0.05 ).In groups C and D,the wet weight of rat lung was significantly lighter compared with groups A and B,and that in group D was lighter compared with C,and that in group B was lighter compared with A 24 h after DDVP poisoning P ＜ 0.05 ).The electron microscopic findings showed the combined use of lipid emulsion with atropine and pralidoxime chloride obviously lessened the lung histopathologic changes after DDVP poisoning.Conclusions The lipid emulsion combined with atropine and pralidoxime chloride can be beneficial to controlling the toxic symptoms,reduce the death rate,accelerate the resume of the activity of CHE in blood,and relieve the lung injury induced by acute organophosphorus poisoning.