INTRODUCTION
Hypotension is a common complication of severe acute organophosphorus poisoning (AOPP).[1,2,3] The mechanism of development of hypotension in patients with AOPP is not fully elucidated. Some studies have found a direct effect of organophosphorus pesticides (OPs) on the cardiovascular system resulting in the decrease in peripheral resistance and impairment of cardiovascular regulation by the central nervous system (CNS).[4,5,6,7] It has also been shown to be an independent predictor of mortality in AOPP patients.[8] Despite the adverse prognostic impact of hypotension, its clinical correlates and associated outcomes have not been investigated in a large and unselected cohort of AOPP patients.
METHODS
Study design
This was a retrospective cohort study of patients with AOPP who were treated at two hospitals in the period between January 1, 2013 and December 31, 2018. The hospital is a referral center for patients with acute poisoning in the Jilin Province. Every year, 500-800 patients with severe poisoning (accidental or intentional) are treated at this hospital.
Diagnosis of AOPP and hypotension
Due to the retrospective study design, the diagnosis of AOPP was based on the documented history of oral intake of OPs and plasma cholinesterase (pChE) level <4,300 U/L at admission, in addition to the characteristic clinical manifestations.
The diagnostic criteria for hypotension were blood pressure less than 90/60 mmHg (1 mmHg=0.133 kPa) and a history of administration of vasopressors, including dopamine or norepinephrine.
Management of AOPP patients
Due to the retrospective nature of this study, the treatment protocol was not standardized. The treatment of individual patients was decided by the treating physician. The typical protocol for AOPP patients was briefly described here. AOPP patients who arrived within 4 hours after OP intake were subjected to gastric lavage with warm water in the absence of any contradictions. Intravenous and intramuscular injections of atropine were used to achieve and maintain the atropinization of patients until the pChE level increased to >2,300 U/L. The usage of oximes depended on the type of OPs. Hemoperfusion was used for decontamination according to the physician’s recommendation, especially in patients with severe poisoning. Hypotensive patients were treated with hemoperfusion only if they remained hemodynamically unstable after treated with vasopressors. Atropinization was described as heart rate >80 beats per minute, clear chest, and cessation of sweating.[9]
Inclusion and exclusion criteria
The inclusion criteria were: (1) patients aged >18 years who qualified the diagnostic criteria for AOPP; (2) patients hospitalized within 24 hours of exposure to OPs. Patients with any of the following features were excluded: (1) patients with poisoning with other drugs in addition to OPs; (2) patients with a normal pChE level (≥4,300 U/L) at admission.
Data collection
All data were retrieved from the electronic in-hospital database of the two referral hospitals. A specially designed questionnaire was used for data collection, which included age, sex, past medical histories (hypertension, diabetes, chronic obstructive pulmonary disease [COPD], chronic kidney disease [CKD], and liver cirrhosis), laboratory tests (white blood cell [WBC] count, pChE, blood urea nitrogen [BUN], albumin, serum amylase, blood pH, and blood lactic acid), cardiac arrest, and usage of hemoperfusion and ventilation. The main outcome was in-hospital mortality. All data were independently collected by two physicians. Any ambiguity with respect to any variable was resolved by consensus. Patients were categorized into two groups depending on the presence or absence of hypotension. The hypotensive group comprised of patients who developed hypotension either before admission or within 24 hours after admission; the remaining patients were categorized as the non-hypotensive group.
Statistical methods
Continuous variables were presented as mean (standard deviation) or median (25th-75th percentile) and between-group differences assessed using the Student’s t-test for normally distributed variables or Mann-Whitney U-test for non-normally distributed variables. Categorical variables were presented as frequency (percentage) and compared using Chi-square test or Fisher’s exact test, as appropriate. Missing variables (including serum amylase, WBC, pH, and lactic acid levels, with relative missing rates of 17.9%, 3.9%, 4.2%, and 4.2%) were imputed 50 times by chained equations. Univariable logistic regression was used to identify variables associated with hypotension; variables associated with P values <0.2 were included in multivariable logistic regression. Multivariable logistic regression was fitted by a backward step-wise method. Survival rates of patients with and without hypotension were compared using the Kaplan-Meier survival method and log-rank test. A univariable Cox proportional hazards model was used to identify parameters associated with mortality. We also used a multivariate proportional hazards model with L2-regulated and 10-fold cross-validation-based iterative determination of covariates to identify the most important parameters associated with mortality. Two-tailed P-values <0.05 were considered indicative of statistical significance. The R packages “survival”,[10] “forestplot”[11] and “glmnet”[12] were used for statistical analyses (R software version 3.6.0).
RESULTS
A total of 1,578 patients with AOPP were identified from the in-hospital databases of the participating hospitals; among them, 707 (44.8%) patients were excluded as they did not qualify the patient-selection criteria: 278 (39.3%) patients were admitted >24 hours after exposure to OPs; 362 (51.2%) patients had concomitant poisoning with other drugs; 67 (9.5%) patients had normal pChE at admission. Finally, a total of 871 patients were included in the analysis. The baseline characteristics of patients from the two hospitals were analyzed and showed a significant difference with respect to WBC counts (P=0.016), levels of albumin (P=0.021), and levels of lactic acid (P=0.017).
Clinical characteristics of patients with and without hypotension
Out of the 871 patients, 143 (16.4%) had hypotension; all patients had developed hypotension before admission or within 24 hours after admission (Table 1). Hypotensive patients were significantly older (50.0 years old vs. 43.0 years old, P<0.001) and were more likely to be diabetic (10.5% vs. 4.0%, P=0.002) than non-hypotensive patients. Patients with hypotension showed significantly lower levels of pChE, albumin, and blood pH. Moreover, patients with hypotension showed significantly higher WBC count, serum amylase, and blood lactate acid. Cardiac arrest was significantly more common in patients with hypotension (0.5% vs. 6.3%, P<0.001). The proportions of patients who received hemoperfusion (48.5% vs. 86.0%, P<0.001) and ventilator support (5.4% vs. 76.9%, P<0.001) in the hypotension group were significantly greater than those in the non-hypotension group. Patients with hypotension experienced significantly higher in-hospital mortality rate than patients without hypotension.
Table 1 Baseline characteristics of the study population disaggregated by the presence or absence of hypotension
| Variables | Overall (n=871) | No hypotension (n=728) | Hypotension (n=143) | P-value |
|---|---|---|---|---|
| Age (years), median (25th-75th percentile) | 44.0 (32.5-56.0) | 43.0 (32.0-54.0) | 50.0 (35.0-66.0) | <0.001 |
| Male, n (%) | 439 (50.4) | 358 (49.2) | 81 (56.6) | 0.123 |
| Past medical history, n (%) | ||||
| Hypertension | 57 (6.5) | 43 (5.9) | 14 (9.8) | 0.096* |
| Diabetes | 44 (5.1) | 29 (4.0) | 15 (10.5) | 0.002 |
| COPD | 7 (0.8) | 3 (0.5) | 4 (2.1) | 0.016* |
| Liver cirrhosis | 3 (0.3) | 2 (0.3) | 1 (0.7) | 0.417* |
| CKD | 7 (0.8) | 4 (0.5) | 3 (2.1) | 0.092* |
| Laboratory test, median (25th-75th percentile) | ||||
| pChE (U/L) | 554 (295-1,460) | 692 (317-1,659) | 302 (193-521) | <0.001 |
| White blood cells (×109/L) | 13.8 (9.5-18.6) | 13.3 (9.2-17.7) | 16.6 (11.3-22.8) | <0.001 |
| Albumin (g/L) | 39.9 (35.9-43.5) | 40.6 (37-43.9) | 34.3 (29.4-39.6) | <0.001 |
| Amylase (U/L) | 104.0 (63.0-248.0) | 91.5 (57.0-183.0) | 248.0 (137.5-544.5) | <0.001 |
| Blood pH | 7.37 (7.31-7.43) | 7.39 (7.34-7.43) | 7.26 (7.15-7.34) | <0.001 |
| Lactic acid (mmol/L) | 1.5 (0.9-3.1) | 1.4 (0.9-2.7) | 2.5 (1.1-5.2) | <0.001 |
| Cardiac arrest, n (%) | 13 (1.5) | 4 (0.5) | 9 (6.3) | <0.001 |
| Hemoperfusion, n (%) | 476 (54.6) | 353 (48.5) | 123 (86.0) | <0.001 |
| Ventilation, n (%) | 149 (17.1) | 39 (5.4) | 110 (76.9) | <0.001 |
| Mortality, n (%) | 65 (7.5) | 8 (1.1) | 57 (39.9) | <0.001 |
COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease; pChE: plasma cholinesterase; *: Fisher’s exact test.
Risk factors for hypotension in AOPP
On univariable logistic regression analysis, the following parameters showed an association with hypotension: advanced age; history of diabetes or COPD; cardiac arrest at presentation; decrease in pChE, plasma albumin, or blood pH; and increase in WBC count, serum amylase, and lactic acid level. Variables associated with P values less than 0.2 were included in multivariable logistic regression. After variable selection by backward step-wise method, advanced age (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.08-1.44), diabetes (OR 2.65, 95% CI 1.14-5.96, P=0.020), increased WBC count (OR 1.06, 95% CI 1.03-1.09, P<0.001), serum amylase (OR 1.01, 95% CI 1.01-1.02, P=0.008), decreased pChE (OR 0.91, 95% CI 0.84-0.94, P<0.001), plasma albumin (OR 0.88, 95% CI 0.85-0.92, P<0.001), and blood pH (OR 0.64, 95% CI 0.54-0.75, P<0.001) were associated with hypotension.
In-hospital mortality and risk factor analysis
Kaplan-Meier survival curves showed a significantly lower survival rate for AOPP patients who had hypotension (log-rank test, P<0.001) (Figure 1). We used the L2-regularized multivariate proportional hazards model to select parameters associated with in-hospital mortality. As shown in Figure 2, three models were fitted according to the variables included in the analysis. Model 1 was fitted with demographic characteristics, past medical history, and treatment parameters. Model 2 was fitted with demographic characteristics and past medical history. Model 3 was fitted with variables that were associated with P values less than 0.05 in model 1. We observed a consistent association of hypotension with increased in-hospital mortality in all the three fitted models (Figure 2), as well as with male sex and diabetes. In the analysis of treatment parameters (model 1 and model 3), ventilation support was also associated with an increased risk of in-hospital mortality.
Figure 1.
Figure 1.
Kaplan-Meier survival curves of acute organophosphorus poisoning patients with and without hypotension.
Figure 2.
Figure 2.
Results of L2-regulated multivariable proportional hazards model showing risk factors for in-hospital mortality of AOPP patients. AOPP: acute organophosphorus poisoning; CKD: chronic kidney disease; CI: confidence interval.
DISCUSSION
In this large cohort study, patients with AOPP who developed hypotension were found to be at a higher risk of in-hospital death. The adjusted hazard ratio for in-hospital mortality in patients with hypotension ranged from 8.77 to 37.06, depending on the existence of confounding factors (Figure 2). Our results are consistent with those of a previous study.[1] These findings indicate the need for appropriate treatment of patients who are at a high risk of hypotension. More studies are needed to develop strategies to decrease the mortality in hypotensive AOPP patients.
On multivariable logistic regression, several parameters were found to be associated with hypotension, including changes in laboratory parameters (WBC count, serum amylase, blood pH, and plasma albumin), advanced age, cardiac arrest, and history of diabetes. The association of advanced age and cardiac arrest with hypotension is entirely plausible, and has been reported earlier.[13] Previous studies have also identified increased serum amylase, increased WBC count, and blood pH as markers of poor prognosis in AOPP patients.[14,15,16] We believe that these changes in laboratory parameters indicate serious organ damage in severe AOPP other than risk factors for hypotension. Of note, diabetes mellitus was found to be a significant risk factor for hypotension and in-hospital death. The underlying mechanism of this association is not well characterized due to the paucity of evidence.
Patients with severe AOPP typically die due to irreversible cardiovascular failure, acidosis, and respiratory failure.[17] With the advances in respiratory management and intensive care, it is possible to maintain the respiratory function of patients with organophosphate poisoning. However, management of hypotension is challenging despite adequate administration of atropine. There is no specific treatment for hypotension in AOPP patients, other than the conventional therapy for shock. However, the conventional therapy is often ineffective in these patients. There is limited evidence available pertaining to the treatment of irreversible hypotension in AOPP patients.
OPs bind irreversibly to acetylcholinesterase in the cholinergic synapses of central and peripheral nerve systems; this results in overstimulation of nicotinic acetylcholine and muscarinic acetylcholine (mACh) receptors in the CNS, neuromuscular junctions, and autonomic nervous system.[18,19] Patients with severe AOPP may develop hypotension due to the overstimulation of muscarinic acetylcholine receptors in the parasympathetic system.[9] In previous studies, patients with severe organophosphate poisoning complicated by hypotension showed low total peripheral resistance and maintained cardiac output.[4,5] The use of catecholamines was ineffective and did not increase the systemic vascular resistance index.[5] This may be attributable to impaired cardiovascular regulation by the CNS through a complex mechanism and depend on the various brain sites and/or actions of different acetylcholine (ACh) receptors. For example, microinjection of mevinphos in the rostral ventrolateral medulla of anesthetized Sprague-Dawley rats induced progressive hypotension that was accompanied by an increase (phase I), followed by a decrease (phase II) in the experimental index of baroreflex-mediated sympathetic vasomotor tone, resulting in a fatality rate of 35%.[20] The activation of mACh receptors in the rostral ventrolateral medulla resulted in a significant increase in mean arterial pressure (MAP) and heart rate (HR),[21] whereas microinjection of ACh into the ventrolateral periaqueductal gray areas and cuneiform nucleus caused a significant depression in MAP with no striking alteration in HR.[22] ACh microinjection or muscarinic receptor activation in the cerebellar cortex was shown to induce marked down-regulation of systemic MAP and HR.[6,7] These findings highlight the importance of CNS in the development of hypotension in AOPP patients.
In this context, we highlight the need for further study on the standards pertaining to atropinization in severe AOPP patients. Although atropine shows moderate penetration in the CNS, it is the mainstay of therapy for AOPP. For patients with hypotension, excess doses of atropine may be required to reverse their hypotension; this should take precedence over control of other muscarinic symptoms.[4] Thus, the routine criteria for atropinization may not be suitable for patients with severe AOPP. The correct standard of atropinization is to provide early and sufficient atropine to prevent hypotension. Future studies should evaluate the fundamentals of atropinization in patients with severe AOPP.
Study limitations
This was a retrospective observational study, and hence subject to incomplete or missing information. We did not include the types and doses of organophosphates in the analysis, because these data were either missing (data pertaining to specific types of organophosphates) or ambiguous (dose often mentioned as “half bottle” or “a few sips”). Data pertaining to the timing of occurrence of hypotension were not available for all patients; therefore, this aspect was not included in the analysis. Moreover, we included only data after admission, and many patients had received ventilation and vasopressor treatment prior to their hospital admission. Lastly, the retrospective study design did not permit any causal inferences.
CONCLUSIONS
Hypotension is a serious and common complication of AOPP and is associated with increased in-hospital mortality. Advanced age, history of diabetes, and deranged laboratory parameters were associated with hypotension in AOPP patients. Optimal management of hypotension is a key imperative to improve patient outcomes.
Funding: None.
Ethical approval: The study protocol was approved by the Medical Ethics Committee of the First Hospital of Jilin University (approval number: 2018-146).
Conflicts of interest: None.
Contributors: ND and ZXL contributed equally to this work. LP and JHX were involved in study conception, study design, and manuscript editing; ND and ZXL analyzed the data, reviewed the literature, and drafted the manuscript; XLL and WL prepared the data and validated the statistical results.
Reference
Heart rate-corrected QT interval helps predict mortality after intentional organophosphate poisoning
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INTRODUCTION: In this study, we investigated the outcomes for patients with intentional organophosphate poisoning. Previous reports indicate that in contrast to normal heart rate-corrected QT intervals (QTc), QTc prolongation might be indicative of a poor prognosis for patients exposed to organophosphates. METHODS: We analyzed the records of 118 patients who were referred to Chang Gung Memorial Hospital for management of organophosphate poisoning between 2000 and 2011. Patients were grouped according to their initial QTc interval, i.e., normal (<0.44 s) or prolonged (>0.44 s). Demographic, clinical, laboratory, and mortality data were obtained for analysis. RESULTS: The incidence of hypotension in patients with prolonged QTc intervals was higher than that in the patients with normal QTc intervals (P = 0.019). By the end of the study, 18 of 118 (15.2%) patients had died, including 3 of 75 (4.0%) patients with normal QTc intervals and 15 of 43 (34.9%) patients with prolonged QTc intervals. Using multivariate-Cox-regression analysis, we found that hypotension (OR = 10.930, 95% CI = 2.961-40.345, P = 0.000), respiratory failure (OR = 4.867, 95% CI = 1.062-22.301, P = 0.042), coma (OR = 3.482, 95% CI = 1.184-10.238, P = 0.023), and QTc prolongation (OR = 7.459, 95% CI = 2.053-27.099, P = 0.002) were significant risk factors for mortality. Furthermore, it was revealed that non-survivors not only had longer QTc interval (503.00+/-41.56 versus 432.71+/-51.21 ms, P = 0.002), but also suffered higher incidences of hypotension (83.3 versus 12.0%, P = 0.000), shortness of breath (64 versus 94.4%, P = 0.010), bronchorrhea (55 versus 94.4%, P = 0.002), bronchospasm (50.0 versus 94.4%, P = 0.000), respiratory failure (94.4 versus 43.0%, P = 0.000) and coma (66.7 versus 11.0%, P = 0.000) than survivors. Finally, Kaplan-Meier analysis demonstrated that cumulative mortality was higher among patients with prolonged QTc intervals than among those with normal QTc intervals (Log-rank test, Chi-square test = 20.36, P<0.001). CONCLUSIONS: QTc interval helps predict mortality after intentional organophosphate poisoning.
Cardiac manifestations of acute carbamate and organophosphate poisoning
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OBJECTIVE: To study the frequency, extent, and pathogenesis of the cardiac complications accompanying organophosphate and carbamate poisoning. DESIGN: Retrospective study. SETTING: A medical intensive care unit (MICU) of a general hospital. SUBJECTS: 46 adult patients admitted over a five year period with a diagnosis of organophosphate or carbamate poisoning. RESULTS: Cardiac complications developed in 31 patients (67%). These were: non-cardiogenic pulmonary oedema, 20 (43%); cardiac arrhythmias, 11 (24%); electrocardiographic abnormalities including prolonged Q-Tc interval, 31 (67%); ST-T changes, 19 (41%); and conduction defects, 4 (9%). Sinus tachycardia occurred in 16 patients (35%) and sinus bradycardia in 13 (28%). Hypertension developed in 10 patients (22%) and hypotension in eight (17%). Eight patients (17%) needed respiratory support because of respiratory depression. Although more than two thirds of the patients (67%) had a prolonged Q-Tc interval, none had polymorphic ventricular tachycardia of the torsade de pointes type. Two patients died from ventricular fibrillation, an in hospital mortality of 4%. CONCLUSIONS: Cardiac complications often accompany poisoning with these compounds, particularly during the first few hours. Hypoxaemia, acidosis, and electrolyte derangements are major predisposing factors. Intensive supportive treatment in intensive or coronary care facilities with administration of atropine in adequate doses early in the course of the illness will reduce the mortality.
A prospective study on electrocardiographic findings of patients with organophosphorus poisoning
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Organophosphate (OP) compounds are widely used in different applications including agriculture. The widespread use of OP insecticides, however, brings high risks of severe health problems. Besides occupational poisoning in industrial production and agricultural application, instances of acute organophosphate poisoning (OPP) also include suicide, homicide, and accidental overdose. Cardiovascular manifestations frequently accompany exposure to these organophosphorus compounds, but their exact nature is not fully elucidated. In this study, we evaluated 20 patients who presented to our emergency department with organophosphorus (OP) poisoning and discussed their associated electrocardiographic (ECG) abnormalities. Over 3 months, 20 patients with OP poisoning were included in this prospective study. ECG analysis included the rate, ST-T abnormalities, conduction defects, and measurement of PR and
Organophosphate poisoning: peripheral vascular resistance: a measure of adequate atropinization
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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.
Changes in the hemodynamic state of patients with acute lethal organophosphate poisoning
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The main cause of death due to acute organophosphate poisoning is believed acute respiratory failure caused by peripheral and central cholinergic actions. Today, advances in respiratory management and intensive care make it possible to maintain the respiratory function of patients with organophosphate poisoning, but it is still difficult to maintain their circulation, and some patients with acute organophosphate poisoning die of metabolic acidosis. The present study clarified the hemodynamics of patients with acute lethal organophosphate poisoning. Subjects were patients with severe acute organophosphate poisoning accompanied by hypotension in whom hemodynamics were monitored by pulmonary artery catheterization. In this study, the medical records of these patients were reviewed. Four patients with severe acute organophosphate poisoning accompanied by hypotension and metabolic acidosis died. In 3/4 patients respiration was maintained favorably. In all 4 patients cardiac output was maintained, but systemic vascular resistance index (SVRI) was significantly reduced. Catecholamine administration was ineffective and did not increase SVRI.
Muscarinic acetylcholine receptor in cerebellar cortex participates in acetylcholine-mediated blood depressor response in rats
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Our previous investigations have revealed that cerebellar cholinergic innervation is involved in cardiovascular regulation. This study was performed to examine the effects of the muscarinic cholinergic receptor (mAChR) in the cerebellar cortex on blood pressure (BP) modulation in rats. Acetylcholine (ACh, 100mM), nonselective mAChR agonist (oxotremorine M; Oxo-M, 10, 30 and 100mM) and 100mM ACh mixed with nonselective mAChR antagonist atropine (1, 3 and 10mM) were microinjected into the cerebellar cortex of anesthetized rats. Mean arterial pressure (MAP), maximal decreased MAP (MDMAP), and reaction time (duration required for BP to return to basal values) were measured and analyzed. The results showed that Oxo-M dose-dependently decreased MAP, increased MDMAP, and prolonged reaction time, which displayed a homodromous effect of ACh-mediated blood depressor response; meanwhile, atropine concentration-dependently blocked the effect of ACh on the BP regulation. In conclusion, the present study showed for the first time that mAChRs in cerebellar cortex could modulate somatic BP by participation in ACh-mediated depressor response.
Role of muscarinic acetylcholine receptor-2 in the cerebellar cortex in cardiovascular modulation in anaesthetized rats
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Our previous investigations have demonstrated that microinjection of acetylcholine (ACh) or muscarinic ACh receptor activation in the cerebellar cortex induces a systemic blood pressure depressor response. This study aimed to determine the role of muscarinic ACh receptor-2 (M2 receptor) in the cerebellar cortex in cardiovascular function regulation in rats. A nonselective muscarinic receptor agonist (oxotremorine M, OXO; 30 mM), a selective M2 receptor agonist (arecaidine but-2-ynyl ester tosylate, ABET; 3, 10, and 30 mM), 30 mM OXO mixed with a selective M2 receptor antagonist (methoctramine hydrate, MCT; 0.3, 1, and 3 mM), and normal saline (0.9 % NaCl) were separately microinjected (0.5 microl/5 s) into the cerebellar cortex (lobule VI) of anaesthetized rats. We measured the mean arterial pressure (MAP), maximum change in MAP, and reactive time (RT; the duration required for the blood pressure to return to basal levels), heart rate (HR) and the maximum change in HR during the RT in response to drug activation. The results demonstrated that ABET dose-dependently decreased MAP and HR, increased the maximum change in MAP and the maximum change in HR, and prolonged the RT. Furthermore, MCT dose-dependently blocked the OXO-mediated cardiovascular depressor response. This study provides the first evidence that M2 receptors in the cerebellar cortex are involved in cardiovascular regulation, the activation of which evokes significant depressor and bradycardic responses.
Hypotension in severe dimethoate self-poisoning
Management of acute organophosphorus pesticide poisoning
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Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available. Medical management is difficult, with case fatality generally more than 15%. We describe the limited evidence that can guide therapy and the factors that should be considered when designing further clinical studies. 50 years after first use, we still do not know how the core treatments--atropine, oximes, and diazepam--should best be given. Important constraints in the collection of useful data have included the late recognition of great variability in activity and action of the individual pesticides, and the care needed cholinesterase assays for results to be comparable between studies. However, consensus suggests that early resuscitation with atropine, oxygen, respiratory support, and fluids is needed to improve oxygen delivery to tissues. The role of oximes is not completely clear; they might benefit only patients poisoned by specific pesticides or patients with moderate poisoning. Small studies suggest benefit from new treatments such as magnesium sulphate, but much larger trials are needed. Gastric lavage could have a role but should only be undertaken once the patient is stable. Randomised controlled trials are underway in rural Asia to assess the effectiveness of these therapies. However, some organophosphorus pesticides might prove very difficult to treat with current therapies, such that bans on particular pesticides could be the only method to substantially reduce the case fatality after poisoning. Improved medical management of organophosphorus poisoning should result in a reduction in worldwide deaths from suicide.
A package for survival analysis in R
Forestplot: advanced forest plot using “grid” graphics
Regularization paths for Cox’s proportional hazards model via coordinate descent
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Plasma cholinesterase activity and clinical course in geriatric organophosphate poisoning
The clinical significance of hyperamylasemia in organophosphate poisoning
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OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Diagnostic value of complete blood count in paraquat and organophosphorus poisoning patients
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Acid-base interpretation as a predictor of outcome in acute organophosphate poisoning
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Respiratory complications of organophosphorus nerve agent and insecticide poisoning. Implications for respiratory and critical care
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Organophosphate and carbamate poisoning
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Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors. Some OP and carbamates have therapeutic indications such as physostigmine. Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents. Both classes inhibit acetylcholinesterase (AChE) enzymes, leading to excess acetylcholine accumulation at nerve terminals. In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation. The toxic effects from OPs and carbamates differ with respect to reversibility, subacute, and chronic effects. Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management.
Hazardous chemical emergencies and poisonings
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PMID:23824088
[Cited within: 1]
As the most widely used pesticides in the world, fatal incidence of suicidal poisoning by organophosphate compounds is high and is often associated with cardiovascular toxicity. Using the pesticide mevinphos as our tool, we investigated the roles of oxidative stress and nitrosative stress at the rostral ventrolateral medulla (RVLM), the brain stem site that maintains arterial pressure (AP) and sympathetic vasomotor tone, in the cardiovascular depressive effects of organophosphate poisons. Microinjection of mevinphos (10 nmol) into the RVLM of anesthetized Sprague-Dawley rats induced progressive hypotension that was accompanied by an increase (phase I), followed by a decrease (phase II) of an experimental index of baroreflex-mediated sympathetic vasomotor tone, with a fatality rate of 35%. During phase I, there was a preferential upregulation of angiotensin type I receptor (AT1R) messenger RNA (mRNA) and protein that leads to activation of NADPH oxidase (Nox) and increase in superoxide at the RVLM. Pharmacological antagonism of these signals exacerbated fatality and shorted survival time by eliminating baroreflex-mediated sympathetic vasomotor tone, AP, and heart rate. During phase II, there was a progressive upregulation of angiotensin type II receptor (AT2R) mRNA and protein that leads to increase in peroxynitrite in the RVLM, blockade of both sustained brain stem cardiovascular regulation and improved survival. We further found that AT1R and AT2R cross-interacted at transcriptional and signaling levels in the RVLM. We conclude that a transition from AT1R-mediated oxidative stress to AT2R-mediated nitrosative stress in the RVLM underlies the shift from sustained to impaired brain stem cardiovascular regulation that underpins cardiovascular fatality during mevinphos intoxication.
Differential muscarinic receptor gene expression levels in the ventral medulla of spontaneously hypertensive and Wistar-Kyoto rats: role in sympathetic baroreflex function
URL PMID:19402224 [Cited within: 1]
Pharmacological study of cholinergic system on cardiovascular regulation in the cuneiform nucleus of rat
DOI:10.1016/j.neulet.2013.05.046
URL
PMID:23811029
[Cited within: 1]
In the present study the effect of cholinergic system of Cuneiform nucleus (CnF) on central regulation of cardiovascular system was investigated. Two doses of acetylcholine (Ach; 90 and 150 nmol), atropine (3 and 9 nmol) and hexamethonium (Hexa; 100 and 300 nmol) were microinjected into the CnF. The maximum changes of MAP and HR were compared with control group (independent t-test). Both doses of Ach significantly decreased MAP but had no significant effect on HR. Administration of atropine and Hexa by themselves did not alter the MAP or HR. However, both doses of atropine and higher dose of Hexa significantly attenuated the hypotensive effect of Ach with no significant effect on HR. Our results suggest the involvement of CnF cholinergic system only on central blood pressure regulation that strongly mediated by muscarinic receptors.
