Evaluation Of Central Nervous System Damage In Acute Phase And The Relationship Between Glucocorticoid And Clinical Outcome Of Diquat Intoxication

Background and ObjectiveIn the clinical practice of patients with acute diquat intoxication,it is found that patients will appear central nervous system symptoms in the acute stage,and their mortality is significantly higher than that of those who are not.Therefore,the central nervous system damage induced by diquat has become a key factor affecting the clinical outcome and prognosis of patients.At the same time,glucocorticoids have been widely used in the treatment of patients with acute diquat intoxication.However,on the basis of early active gastric lavage,catharsis and blood purification,the dose selection of glucocorticoids in patients with,acute paraquat poisoning and whether it can improve clinical outcomes remain controversial.Therefore,the application of glucocorticoids in the treatment of patients with acute diquat intoxication has become an important issue of concern to clinicians.As far as we know,the neurotoxic mechanism of diquat is still unclear,and the characteristics of central nervous system damage caused by diquat after acute poisoning in vivo have not been reported.In the treatment of patients with acute diquat intoxication,the dose selection of glucocorticoids and whether it can improve the clinical outcome of patients are also lacking relevant evidence.In this study,the characteristics of central nervous system damage in SD rat model with acute diquat intoxication were evaluated and a retrospective analysis of clinical data of acute paraquat and diquat intoxication in the real world were conducted to study the neurocytotoxicity characteristics of acute diquat intoxication and the application strategy of glucocorticoids in clinical treatment.Part 1Evaluation of the application value of magnetic resonance diffusion kurtosis imaging in the central nervous system damage of SD rats in the acute stage of diquat poisoningBackground and ObjectiveSince China banned the sale and use of paraquat in 2014,the number of patients suffering from acute diaquat poisoning has increased.In clinical practice,it is found that the fatality rate of acute diquat intoxication is still high,and the central nervous system symptoms,such as drowsiness,epileptic seizure,intracranial hemorrhage and so on,can occur in the acute stage.Based on the summary of the case data in the previous literature,it was found that the short-term mortality of patients with acute diquat intoxication was significantly higher than that of those without consciousness disturbance in the acute stage.Therefore,the mechanism of central nervous system injury caused by acute diquat intoxication has become a hot issue.However,it is not clear how diquat crosses the blood-brain barrier into the central nervous system and whether it selectively destroys nerve cells.Diffusion Kurtosis imaging(DKI)is a new practical technology to reflect the diffusion imaging of non-Gaussian distribution of water molecules in tissues.It is more sensitive to detect the diffusion movement of water molecules in the human microenvironment and can provide more abundant diffusion information.DKI can obtain the anisotropy fraction(FA),the mean diffusion(MD)and the mean kurtosis(MK)value representing the kurtosis imaging.These values are correlated with the structural complexity of the corresponding parts,which provides us with a quantitative test method to understand the central nervous system damage in the acute stage of acute diquat intoxication.In this study,we established a model of acute diquat moderate poisoning in SD rats,scanned the brain with DKI technique,and evaluated the effect of diquat on the central nervous system in combination with serum nerve cell injury markers and brain histopathology.MethodsThirty-two healthy adult male clean grade SD rats were randomly divided into 4 groups,namely blank group and 12h,24h and 72h after exposure,with 8 rats in each group.The experimental rats were given intragastrically at a dose of diquat standard product(200mg/kg)once and the control group was treated with the same amount of normal saline.After successful modeling,the rats in each group were scanned by magnetic resonance diffusion kurtosis imaging under deep anesthesia,and the rats in the 12h post-exposure group were also scanned at 1h,3h and 6h post-exposure.The anisotropy fraction,average diffusion coefficient and average kurtosis of the brain regions of interest were obtained by functional magnetic resonance imaging post-processing software.After scanning,aorta blood was extracted immediately,supernatant was taken after centrifugation,and serum NSE and S-100B were detected by ELISA.The whole brain of the rats was decapitated and soaked in 4%paraformaldehyde overnight.H&E staining and TUNEL fluorescence staining were performed to observe the morphological changes and apoptosis of nerve cells in the substantia nigra,striatum,hippocampus and cerebral cortex.ResultsThere were no relevant neurological symptoms appeared in each poisoned group during the study period.DKI presented that there was no obvious lateral difference in the toxicity of diquat to central nervous system of rats.There were significant changes of DKI parameters in striatum,substantia nigra,hippocampus,cerebral cortex and thalamus,especially FA and MK values were more sensitive than MD values.There were no statistically significant changes in hindbrain and cerebellum during the study period.There was no statistically significant difference in serum NSE among all groups,while S100B in the 72h group after poisoning increased gradually with the time of poisoning,and the difference was statistically significant compared with the blank group.H&E staining revealed progressive nuclear morphologic changes in the striatum,substantia nigra,hippocampus and cerebral cortex,with no apoptosis shown by TdT-mediated dUTP Nick-End Labeling fluorescence staining.Conclusions1.Diquat can induces extensive neurotoxicity without apoptosis in the acute phase.2.Diffusion kurtosis imaging may be more sensitive to central nervous system lesions than plain sequence and diffusion tensor imaging.Part 2The relationship between glucocorticoid and clinical outcome of patient in acute diquat or paraquat intoxication based on propensity score matching in the real worldAbstractBackground and ObjectiveAcute diquat(DQ)or paraquat(PQ)poisoning is an international clinical and public health problem that cannot be ignored.Paraquat and diquat both belong to bipyridine contact herbicides and have been widely used in agricultural production in China.There is a high incidence of morbidity and mortality in acute intoxication due to suicide or accidental ingestion.In 2014,China banned the production and sale of paraquat,followed by an increasing number of cases of acute diquat poisoning.The combination of the two poisons is also common as unsold paraquat is added to some products or sold as diquat.Existing studies suggest that diquat and paraquat cause tissue and cell damage mainly by promoting the accumulation of intracellular superoxide anion free radicals and inducing oxidative stress reaction and lipid peroxidation of cell membrane,and their toxicity can affect multiple organs in the whole body.Glucocorticoid has been widely used in the treatment of acute poisoning of both groups because of its functions of stabilizing cell lysosomal membrane,inhibiting inflammatory response and anti-pulmonary fibrosis.At present,the dosage of glucocorticoid is still controversial,and there are relatively many studies on the application of shock dose but no consistent conclusions.However,it has not been reported whether the use of lower impact dose can improve the clinical outcome of patients.Based on the clinical data of real world acute paraquat and diquat intoxication,the relationship between paraquat and diquat intoxication was investigated by using propensity score matching method,in order to provide reference for future diagnosis and treatment.MethodsA single-center retrospective clinical study was conducted to analyze the clinical data of 525 patients with acute paraquat or diquat poisoning in the Department of Emergency Medicine,The First Affiliated Hospital of Zhengzhou University from March 2013 to February 2022.According to the results of toxicological screening,they were divided into three groups:single paraquat group,single diquat group and mixed group to analyze differences and similarities in clinical indicators among them.Clinical outcomes were determined based on patients’ in-hospital and 30-day follow-up after discharge.All paraquat poisoning patients were divided into high-dose(≧500mg/d)and low-dose(<500mg/d)groups according to the average daily dose of glucocorticoid to complete propensity score analysis,and subgroup analysis was conducted according to oral dose(≦20ml,21-50ml,51-100ml and>100ml).ResultsOnly the total amount and days of glucocorticoid use in single diquat group were lower than those in single paraquat group(P<0.05),while the oral dose,daily mean glucocorticoid dose and mortality in mixed group were higher than those in single poisoning group(P<0.05).The results of propensity score matching showed that the mortality rate of high-dose glucocorticoid group(74.5%)was significantly higher than that of low-dose group(40.0%)(P=0.000).In the patients with oral dose≦ 20ml,there was no significant difference in the intra-group mortality between the high-dose and low-dose groups(χ2=0.443,P=0.776).With the increase of oral dose,the mortality in the high-dose group gradually increased.Conclusions1.The use of high doses of glucocorticoids(≧=500mg/d)did not reduce mortality in patients with acute paraquat poisoning.2.In view of the similar clinical characteristics in patients with acute diquat and paraquat poisoning within 48 hours after administration,the use of high doses of glucocorticoids(≧500mg/d)is also not recommended for patients with acute single diquat poisoning and mixed poisoning.3.More attention should be paid to patients with mixed poisoning because they are more severe and have higher mortality than those with single poisoning.General conclusions1.Diquat induces extensive neurotoxicity without apoptosis in the acute phase.2.Diffusion kurtosis imaging may be more sensitive to central nervous system lesions than plain sequence and diffusion tensor imaging.3.The use of high doses of glucocorticoids(≧500mg/d)did not reduce mortality in patients with acute paraquat poisoning.4.In view of the similar clinical characteristics in patients with acute diquat and paraquat poisoning within 48 hours after administration,the use of high doses of glucocorticoids(≧500mg/d)is also not recommended for patients with acute single diquat poisoning and mixed poisoning.5.More attention should be paid to patients with mixed poisoning because they are more severe and have higher mortality than those with single poisoning.