Serial serum cholinesterase activities as a prognostic factor in organophosphate poisoned patients

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1 Hong Kong Journal of Emergency Medicine Serial serum cholinesterase activities as a prognostic factor in organophosphate poisoned patients HW Yun, DH Lee, JH Lee, YJ Cheon, YH Choi Objective: Organophosphate poisoning is a serious clinical entity and of considerable morbidity and mortality. Several factors have been identified to predict outcomes of organophosphate poisoning. This investigation aims to identify the relationship between the dynamics of serum cholinesterase () activity and mortality. Methods: In this retrospective study, medical records of all patients with acute organophosphate poisoning were reviewed from January 2001 to December Clinical features, activity, Glasgow Coma Scale, laboratory findings, electrocardiogram finding, management and their outcomes were examined. Results: A total of 169 patients were included in this study. A total of 55 patients were enrolled. Deceased patients were 8 in number. Absence of an increase in activity was related with mortality in organophosphate poisoned patients (p value=0.036; odds ratio, 5.445; 95% confidence interval, ). Conclusions: The absence of an increase in activity is associated with higher mortality in organophosphate poisoning. The dynamic activity can provide a guide to physicians in the evaluation and management of organophosphate poisoned patients. (Hong Kong j.emerg.med. 2012;19:92-97) p = % Keywords: Organophosphorus, pesticide, prognosis, pseudocholinesterase Correspondence to: Choi Yoon Hee, MD Ewha Womans University, Department of Emergency Medicine, Mok-dong 911-1, Yang-ChoenKu, Seoul , South Korea like-lemontea@hanmail.net Yun Hyun Woo, MD Cheon Young Jin, MD Eulji University, Department of Emergency Medicine, Seoul, South Korea Lee Duk Hee, MD Lee Jae Hee, MD Introduction Organophosphate pesticides are widely used in the agricultural setting throughout the world. Organophosphate pesticides account for up to 3 million intoxication cases each year. 1 An estimated 200,000 die in rural Asia where intentional self-harm is common. 2 Many literatures have reported on the various factors that predict the outcome in acute organophosphate

2 Yun et al./serial serum cholinesterase activities 93 poisoning. The recognised predictors of poor outcome include initial blood pressure, Glasgow Coma Scale (GCS) score, serum cholinesterase () level, APACHE II (Acute Physiology and Chronic Health Evaluation II) score, and electrocardiogram findings (prolongation of QT interval). 3-5 activity is often checked in organophosphate poisoned patients. There were many controversial reports in the literature about the relationship between the severity of poisoning and the plasma cholinesterase levels. 6 We aimed to investigate serial activities so as to help clinicians to predict the clinical outcome of organophosphate poisoned patients. Method Patients included in the study followed a standard treatment guideline of organophosphate poisoning in our hospital. Activated charcoal was administered after gastric lavage for all patients. Atropine and pralidoxime (PAM) administration were administrated in accordance with the protocol of the hospital. PAM 1 g was administered as a first loading dose over 30 minutes. After that, PAM was infused continuously (800 mg/hour). Endotracheal intubation or intensive care unit (ICU) admittance was carried out, in compliance with general standards, after obtaining consent from a guardian. We analysed the data of the following variables: demographic factors (date of arrival, sex and age of patient), medical history, history of intoxication (ingredients of organophosphate, time and route of exposure, amount ingested, suicidal intention), clinical manifestations, GCS, initial vital signs (respiratory rate, heart rate, systolic blood pressure), initial blood tests (white blood cell count, haematocrit, platelet count, serum blood urea nitrogen, creatinine, sodium and potassium concentration, amylase, arterial blood gas analysis), activity, electrocardiographic results (corrected QT (QTc) interval), treatments received (duration of atropine and pralidoxime administration, any endotracheal intubation, total duration of mechanical ventilation, total duration of ICU stay, total duration of admission), mortality, and APACHE II score. Cross-tabulation was performed for non-continuous variables using the PASW (SPSS) version 18, and Student t test was used for continuous variables. To analyse the variables multivariate linear regression and multivariate logistic regression analysis (as appropriate) were used. A p-value of less than 0.05 was considered statistically significant. Results We reviewed the medical records of 169 patients and excluded 114 patients meeting the exclusion criteria. Of those patients excluded, there were 2 children, uncertain history of exposure and uncertain agent in 8 patients, 8 patients transferred to other hospitals, 58 patients discharged from emergency department for mild toxicity, carbamate poisoning in 18 patients and absence of initial activity or serial follow-up activity in 20 patients. The total number of subjects that were enrolled was 55. Substances responsible for poisoning were methidathion (n=11), chlorpyrifos (n=10), malathion (n=4), phosphamidon (n=3), dimethoate (n=2), parathion (n=2), fenithrothion (n=2), phentoate (n=2), chlorfluazuron (n=2) and others (Table 1). Table 1. Types of poisoning agents Agent Frequency % Methidathion Chlorpyrifos Malathion Phosphamidon Dimethoate Parathion Fenithrothion Phentoate Chlorfluazuron Others Total

3 94 Hong Kong j. emerg. med. Vol. 19(2) Mar 2012 Univariate analysis for factors that affect mortality Age, sex, time interval from poisoning to hospital, amount of ingestion, systolic blood pressure (SBP), oxygen saturation in blood gas analysis, APACHE II score, initial activity, serial (elevated, not elevated), QTc and GCS were analysed. APACHE II score (p=0.001; odds ratio, 1.285; confidence interval, ) and dynamic changes in activity (p=0.036; odds ratio, 5.445; confidence interval, ) were found to be related to mortality. Absences of an increase in activity are related with mortality in organophosphate poisoned patients. (A) (B) General characteristics of deceased and survival groups in organophosphate poisoned patients The number of deceased and survived patients was 8 and 47 respectively. The causes of death were failure of weaning intubation, aggravated pneumonia and multi-organ failure. The general characteristics of 55 patients of acute organophosphate poisoning, who had checked with serial activity, are summarised in Table 3. There were no significant differences in age (p=0.105), time interval from poisoning to initial activity taken (p=0.208), amount of organophosphate ingested (p=0.254). SBP (p=0.804), initial oxygen saturation (p=0.088) and QTc (p=0.353) were not different between the two groups. Sex (p=0.043) was different in the two group using Chisquare analysis. Deceased patients had a higher APACHE II score (p=0.000) and lower GCS (p=0.004). No statistically significant difference was found between two groups regarding clinical course, such as intubation requirement (p=0.176), mechanical ventilator duration (p=0.898), ICU duration (p=0.284) and total admission duration (p=0.069). The relationship between serial activity and mortality Fisher's exact test was used to examine the relationship between dynamic changes of activity level and mortality and was shown to be statistically significant (p=0.038) (Table 4). The activity slope medium was mu/ml per hour in the deceased group and mu/ml per hour in the survival group (Figure 1). Multivariate logistic regression analysis after adjusting for sex, was the only factor significantly associated with mortality and absences of an increase in serial activity (p=0.043; odds ratio, 5.753; 95% confidence interval, )(Table 5). Table 2. Univariate analysis of factors that affect mortality in organophosphate poisoned patients Variables OR 95% CI p value Age (year) Male/Female Time interval from poisoning to initial activity taken Amount (ml) SBP (mmhg) O2 saturation (%) APACHEII score Initial activity (mu/ml) Serial (elevation, non-elevation) QTc (msec) GCS APACHE=Acute Physiology and Chronic Health Evaluation; CI=confidence interval; GCS=Glasgow Coma Scale; OR=odds ratio; SBP=systolic blood pressure; =serum cholinesterase

4 Yun et al./serial serum cholinesterase activities 95 Table 3. Characteristics of deceased patients and survival patients in organophosphate poisoned patients Variables Deceased group (n=8) Survival group (n=47) p value Age (year), mean±sd 62.88± ± Male/Female, n 2/6 32/ Time interval from poisoning to initial ± ± activity taken (minute), mean±sd Amount (ml), mean±sd 65.83± ± SBP (mmhg), mean±sd ± ± O2 Saturation (%), mean±sd 71.55± ± WBC (ul), mean±sd ± ± Glucose (mmol/l), mean±sd 12.51± ± Amylase (IU/L), mean±sd ± ± APACHEII score, mean±sd 26.00± ± Initial activity (mu/ml), mean±sd ± ± QTc (msec), mean±sd ± ± GCS, mean±sd 7.14± ± PAM duration (day), mean±sd 7.75± ± Intubation requirement, n (%) 8(100) 34(81.0) Mechanical ventilation duration (day), mean±sd 7.75± ± ICU duration (day), mean±sd 7.75± ± Total admission duration (day), mean±sd 7.75± ± APACHE=Acute Physiology and Chronic Health Evaluation; GCS=Glasgow Coma Scale; ICU=intensive care unit; PAM=pralidoxime; QTc=corrected QT interval; SBP=systolic blood pressure; =serum cholinesterase; SD=standard deviation; WBC=white blood cell Table 4. Mortality and serial activity of Deceased Survival p value group group (n=8) (n=47) level elevated 3 36 level not elevated =serum cholinesterase Table 5. Multivariate logistic regression analysis of mortality and serial activity of OR 95% CI p value Serial activity CI=confidence interval; OR=odds ratio; =serum cholinesterase Discussion Organophosphate poisoning is a serious clinical entity and causes considerable mortality and polyneuropathy in survivors. The estimated mortality following organophosphate ingestion ranges from 11 to 23%. 4,6 Organophosphates inhibit the enzyme acetylcholinesterase in the cholinergic synapse and red cells and butyrylcholinesterase in the plasma. The inhibition of cholinesterase leads to acetylcholine accumulation at the nerve synapses and neuromuscular junctions, resulting in an over-stimulation of acetylcholine receptors. The continued stimulation of the acetylcholine receptors leads to the clinical signs and symptoms of organophosphate poisoning. 7,8 Previous studies have reported a relationship between the degree of poisoning and plasma cholinesterase in organophosphate poisoning Low levels are correlated with a poor prognosis. However, Nouira et al reported that there are no correlations between the

5 96 Hong Kong j. emerg. med. Vol. 19(2) Mar 2012 hypoxaemia, bradycardia, and hypotension were associated with a decrease in erythrocyte acetylcholinesterase activity but no correlations were found between erythrocyte acetylcholinesterase and muscarinic and nicotinic signs in 42 patiens. 14 Methods and samples for measurement of cholinesteraase is controversial. Some supported the notion that using whole blood instead of separating red blood cell from plasma minimises the variability of cholinesterase activity in the haemoglobin rich fraction. 15 In contrast, others suggested that plasma cholinesterase is more useful in the early detection of organophosphate toxicity than red cell cholinesterase. 16 Figure 1. Median slopes of the trend of activity in organophosphate poisoned patients. degree of poisoning and the plasma cholinesterase measured on the day of admission. levels measured on admission in 30 patients had no prognostic value in organophosphate poisoning. 9 The measurement of erythrocyte acetylcholinesterase, which reflects inhibition at the muscarinic and nicotinic synapses, is a more reliable and clinically significant parameter in clinical presentation. Erythrocyte acetylcholinesterase could serve as a surrogate biomarker for synaptic acetylcholinesterase. 12,13 Nozha et al reported that coma, mechanical ventilation, activity has a high degree of variability from person to person. 17 is subject to high degree of variation induced by hereditary deficiency of this enzyme, liver function, malnutrition, iron deficiency anaemia, drugs such as cocaine, morphine, codeine and succinylcholine making this enzyme a less-than-perfect biomarker for organophosphate poisoning if baseline levels are unknown in an individual. 14 A single measurement of activity has no prognostic value but serial activities may better predict patient mortality. According to a report, the absence of elevating activity level within 48 hours of poisoning appears to be associated with a higher mortality in acute organophosphate poisoned patients. 17 Today many clinicians are using levels to assess the condition of their patients. As is also practiced in our medical institute, levels are serially measured if the patient does not improve. Many factors have been reported to identify severely poisoned patients and to be correlated with mortality. But their applications in therapy have not yet been studied. In this study, the absence of serial activity was significantly associated with a poor course. Therefore, serial checking of activities can provide physicians to predict the clinical courses and evaluation of organophosphate poisoned patients. This study had several limitations. Only 55 out of the 169 patients were enrolled. A prospective, multicentre study including a longer period could overcome this condition. Besides, various organophosphate agents

6 Yun et al./serial serum cholinesterase activities 97 were involved. Eddleston et al reported that different organophosphates have different chemical characteristics and poisoning outcomes. Chlorpyrifos and dimethoate have different sensitivity for butyrylcholinesterase and the relationship between enzyme inhibition and mortality in one is not applicable to another. 18 Therefore we may get more correct conclusion if more cases of a single agent were recruited. Conclusion The absence of an increase in activity is significantly associated with a higher mortality in organophosphate poisoning patients. Although many factors were reported bearing prognostic value, their importance are not confirmed in this study. Serial measurements can provide a guide to physicians in reevaluation and management in organophosphate poisoning patients. References 1. Thiermann H, Eyer F, Felgenhauer N, Pfab R, Zilker T, Eyer P, et al. Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds. Toxicol Lett 2010;197(3): Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE. Goldfrank's toxicologic emergencies. 9th ed. McGraw Hill; 2011 p Sam KG, Kondabolu K, Pati D, Kamath A, Pradeep Kumar G, Rao PG. Poisoning severity score, APACHE II and GCS: effective clinical indices for estimating severity and predicting outcome of acute organophosphorus and carbamate poisoning. J Forensic Leg Med 2009;16(5): Kang EJ, Seok SJ, Lee KH, Gil HW, Yang JO, Lee EY, et al. Factors for determining survival in acute organophosphate poisoning. Korean J Intern Med 2009; 24(4): Chuang FR, Jang SW, Lin JL, Chern MS, Chen JB, Hsu KT. QTc prolongation indicates a poor prognosis in patients with organophosphate poisoning. Am J Emerg Med 1996;14(5): Aygun D, Doganay Z, Altintop L, Guven H, Onar M, Deniz T, et al. Serum acetylcholinesterase and prognosis of acute organophosphate poisoning. J Toxicol Clin Toxicol 2002;40(7): Akdur O, Durukan P, Ozkan S, Avsarogullari L, Vardar A, Kavalci C, et al. Poisoning severity score, Glasgow coma scale, corrected QT interval in acute organophosphate poisoning. Hum Exp Toxicol 2010; 29(5): Robey WC III, Meggs WJ. Pesticides. In Tintinalli's emegency medicine: a comprehensive study guide. 7th ed. McGraw-Hill and ACEP; p Nouira S, Abroug F, Elatrous S, Boujdaria R, Bouchoucha S. Prognostic value of serum cholinesterase in organophosphate poisoning. Chest 1994;106(6): Merill DG,MihmFG. Prolonged toxicity of organophosphate poisoning. Crit Care Med 1982;10 (8): Routier RJ, Lipman J, Brown K. Difficulty in weaning from respiratory support in a patient with the intermediate syndrome of organophosphate poisoning. Crit Care Med 1989;17(10): Hassan RM, Pesce AJ, Sheng P, Hanenson IB. Correlation of serum pseudocholinesterase and clinical course in two patients poisoned with organophosphate insecticides. Clin Toxicol 1981;18(4): Brahmi N, Mokline A, Kouraichi N, Ghorbel H, Blel Y, Thabet H, et al. Prognostic value of human erythrocyte acetylcholinesterase in acute organophosphate poisoning. Am J Emerg Med 2006;24(7): Kolf-Clauw M, Jez S, Ponsart C, Delamanche IS. Acetyl- and pseudo-cholinesterase activities of plasma, erythrocytes, and whole blood in male beagle dogs using ellman's assay. Vet Hum Toxicol 2000;42(4): Sakr Y, Madl C, Filipescu D, Moreno R, Groeneveld J, Artigas A, et al. Obesity is associated with increased morbidity but not mortality in critically ill patients. Intensive Care Med 2008;34(11): Orluwene CG, Ejilemele AA. Comparison of red cell cholinesterase and plasma cholinesterase activities in early detection of organo-phosphorus toxicity in exposed industrial workers in Port Harcourt, Nigeria. Niger J Med 2006;15(3): Chen HY, Wang WW, Chaou CH, Lin CC. Prognostic value of serial serum cholinesterase activities in organophosphate poisoned patients. Am J Emerg Med 2009;27(9): Eddleston M, Eyer P, Worek F, Sheriff MH, Buckley NA. Predicting outcome using butyrylcholinesterase activity in organophosphorous pesticide self-poisoning. QJM 2008;101(6):